{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Somatic Mutation Theory of Cancer", "entry_form": "phenomenon", "gradeable_restatement": "Sequential somatic driver mutations are the primary initiating and sustaining cause of cancer.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Histology, tissue lineage, germline versus somatic origin, driver genotype and alteration class, disease stage and treatment exposure", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Somatic Mutation Theory of Cancer", "central_claim": "Sequential somatic driver mutations are the primary initiating and sustaining cause of cancer.", "proposed_mechanism": "Sequential somatic driver mutations are the primary initiating and sustaining cause of cancer.", "claimed_scope": "Sequential somatic driver mutations are the primary initiating and sustaining cause of cancer.", "claimed_level": [ "initiation", "maintenance" ], "is_conjunctive": true, "conjunctive_note": "Use the index nominal strong claim. Grade mutation presence, causal dependency and cross-cancer primacy separately. Specific mutation-dependent cancers are reported on their own terms; the broad primacy gate is SC3. Normal mutant clones and defined epigenetic/tissue exceptions must be reconciled without recapping a convergent genetic/therapeutic set." }, "rubric_routing": { "primary_rubric": "02-cancer-biology.md", "secondary_rubrics": [ "03-epigenetics-gene-regulation.md" ], "index_notes_applied": [ "Use the index nominal strong claim. Grade mutation presence, causal dependency and cross-cancer primacy separately. Specific mutation-dependent cancers are reported on their own terms; the broad primacy gate is SC3. Normal mutant clones and defined epigenetic/tissue exceptions must be reconciled without recapping a convergent genetic/therapeutic set." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Recurrent somatic driver mutations can be distinguished from passengers in specific cancers.", "subclaim_type": "existence", "scope": "prespecified cancer histologies and mutation classes", "claimed_scope": "prespecified cancer histologies and mutation classes", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Genomic selection and matched functional validation", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Recurrent alterations are distinguished from passengers by selection, clonal timing and precise functional perturbations in specific histologies. Independent genome platforms and autochthonous editing reduce sequencing-error and correlation-only explanations. Genomic annotation alone remains insufficient, and fitness in normal tissue is not necessarily cancer-driving fitness. Ζ is supported across assay classes; most claimed variant classes have not individually received therapeutic/endogenous confirmation, so Η is not assigned to every driver-identification inference." }, { "id": "SC2", "statement": "Driver mutations are causal dependencies for initiation or maintenance in defined cancers.", "subclaim_type": "necessity", "scope": "genotype-defined cancer models and patients", "claimed_scope": "genotype-defined cancer models and patients", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Endogenous mutation loss/restoration and driver-targeted hard clinical outcomes", "hsef_level": "Η", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Endogenous Kras combinations, endogenous p53 restoration, reversible APC loss/restoration and lineage-marked tumor differentiation establish causal dependencies in defined cancers. Multiple genotype-selected clinical trials yield progression or survival consequences across EGFR, BRAF, RET, ALK and BCR-ABL settings. These complementary lines fail differently and satisfy Η in the prespecified genotype-defined scope. The subclaim is initiation OR maintenance, not a requirement that each report establish both. Residual states, relapse and incomplete target response prevent Θ/Ω for most cancer behavior or universal necessity/sufficiency." }, { "id": "SC3", "statement": "Sequential somatic driver mutations are the dominant initiating and sustaining cause across cancer.", "subclaim_type": "primacy", "scope": "cancer broadly, with tissue and histology set before outcome", "claimed_scope": "cancer broadly, with tissue and histology set before outcome", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Mutation-versus-tissue/epigenetic perturbations across representative cancers", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Genetic alterations are primary drivers in many tested cancers, with causal initiation and ongoing dependency, rather than mere passengers. Their phenotypic output depends on lineage, niche, immunity and chromatin; tissue mediation may be downstream of the genetic lesion and is not automatically an exclusive rival. Normal mutant tissues show insufficiency, fly/reprogramming models demonstrate bounded alternative initiation, and relapse can change dependence. Ε credits the real causal model while restricting the broad dominant-sequential initiating-and-sustaining claim. This is not a finding that common cancers generally lack driver mutations." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "Use the index nominal strong claim. Grade mutation presence, causal dependency and cross-cancer primacy separately. Specific mutation-dependent cancers are reported on their own terms; the broad primacy gate is SC3. Normal mutant clones and defined epigenetic/tissue exceptions must be reconciled without recapping a convergent genetic/therapeutic set.", "primary_subclaim_id": "SC3", "aggregation_derivation": "The preregistered scope-matched SC3 gate returns Ε: causal validity with explicit context limits. Driver identification reaches Ζ and defined initiation/maintenance dependencies reach Η through endogenous autochthonous genetics, restoration/rechallenge, human genomic natural history and genotype-selected hard clinical outcomes. The set is not re-capped by culture or xenograft limitations. Broad primacy requires a representative comparison of mutation, tissue and cell-state causation across initiation, maintenance and relapse; that burden is not established by genetic relevance alone. Benign driver clones challenge sufficiency, not the strong causal genetic evidence.", "aggregation_alternatives": { "weakest_link_would_return": "Ε", "primary_subclaim_would_return": "Ε", "scope_matched_would_return": "Ε", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Integrated mutation–tissue model", "core_claim": "Genetic lesions, lineage, niche and regulatory state jointly determine specified cancer behavior.", "explains_what_nominal_does_not": "Genetic lesions, lineage, niche and regulatory state jointly determine specified cancer behavior.", "strongest_supporting_evidence": [ "Endogenous APC/NOTUM, context-dependent autochthonous editing, immune-dependent oncogene regression, PM/IL1 promotion and fibroblast depletion show functional interactions across assay classes." ], "strongest_contradictory_evidence": [ "Ζ applies to these specified interactions; an unrestricted flexible umbrella is not a tested universal model or proof that tissue changes precede all mutations." ], "hsef_level_for_this_model": "Ζ", "rationale": "Endogenous APC/NOTUM, context-dependent autochthonous editing, immune-dependent oncogene regression, PM/IL1 promotion and fibroblast depletion show functional interactions across assay classes. Ζ applies to these specified interactions; an unrestricted flexible umbrella is not a tested universal model or proof that tissue changes precede all mutations." }, { "rank_in_tournament": 2, "model_id": "M1", "is_nominal": true, "name": "Somatic mutation primacy", "core_claim": "Sequential somatic drivers dominate cancer initiation and maintenance across cancers.", "explains_what_nominal_does_not": "Sequential somatic drivers dominate cancer initiation and maintenance across cancers.", "strongest_supporting_evidence": [ "Strong endogenous genetic dependencies and genotype-directed survival/progression benefits support many defined contexts." ], "strongest_contradictory_evidence": [ "Normal driver-bearing tissues, state plasticity, epigenetic initiation and stage-specific dependencies leave broad dominance incompletely tested." ], "hsef_level_for_this_model": "Ε", "rationale": "Strong endogenous genetic dependencies and genotype-directed survival/progression benefits support many defined contexts. Normal driver-bearing tissues, state plasticity, epigenetic initiation and stage-specific dependencies leave broad dominance incompletely tested." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Nongenetic malignant states", "core_claim": "Chromatin and differentiation memory can initiate or sustain malignant/tolerant states in specified contexts.", "explains_what_nominal_does_not": "Chromatin and differentiation memory can initiate or sustain malignant/tolerant states in specified contexts.", "strongest_supporting_evidence": [ "Transient fly Polycomb depletion, interrupted reprogramming and reversible drug tolerance demonstrate functional state plasticity." ], "strongest_contradictory_evidence": [ "Developmental perturbation and culture are not evidence that ordinary human cancer generally lacks genetic drivers; tolerance is not original cancer initiation." ], "hsef_level_for_this_model": "Ε", "rationale": "Transient fly Polycomb depletion, interrupted reprogramming and reversible drug tolerance demonstrate functional state plasticity. Developmental perturbation and culture are not evidence that ordinary human cancer generally lacks genetic drivers; tolerance is not original cancer initiation." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Chromosomal instability first", "core_claim": "Chromosome instability can initiate or facilitate escape in defined models.", "explains_what_nominal_does_not": "Chromosome instability can initiate or facilitate escape in defined models.", "strongest_supporting_evidence": [ "Transient Mad2-induced tumors and Kras-independent relapse support a bounded instability route." ], "strongest_contradictory_evidence": [ "Chromosome changes are genetic; forced checkpoint perturbation and sparse context coverage do not establish universal temporal primacy." ], "hsef_level_for_this_model": "Ε", "rationale": "Transient Mad2-induced tumors and Kras-independent relapse support a bounded instability route. Chromosome changes are genetic; forced checkpoint perturbation and sparse context coverage do not establish universal temporal primacy." }, { "rank_in_tournament": 5, "model_id": "M3", "is_nominal": false, "name": "Tissue organization field theory", "core_claim": "Tissue disorganization is the primary initiating and sustaining cause across cancers.", "explains_what_nominal_does_not": "Tissue disorganization is the primary initiating and sustaining cause across cancers.", "strongest_supporting_evidence": [ "Compartment recombination, stromal normalization and integrin/context reversal support contextual causal leads." ], "strongest_contradictory_evidence": [ "Transplantation, limited mutation exclusion and heterogeneous stromal effects do not establish a universal endogenous tissue-first dependency; strong genetic dependencies remain." ], "hsef_level_for_this_model": "Γ", "rationale": "Compartment recombination, stromal normalization and integrin/context reversal support contextual causal leads. Transplantation, limited mutation exclusion and heterogeneous stromal effects do not establish a universal endogenous tissue-first dependency; strong genetic dependencies remain." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Use factorial mutation correction/restoration and defined niche/state perturbation in the same native lineage, with lineage-traced malignant endpoints, maintained viability and mutation-sensitive monitoring. An integrated model must make prespecified interaction predictions; flexibility alone cannot win.", "study_separating_rank1_from_rank2": "Use factorial mutation correction/restoration and defined niche/state perturbation in the same native lineage, with lineage-traced malignant endpoints, maintained viability and mutation-sensitive monitoring. An integrated model must make prespecified interaction predictions; flexibility alone cannot win.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "5279523", "title": "Mutation and cancer: statistical study of retinoblastoma.", "citation": "Knudson AG et al. Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America. 1971.", "doi": "10.1073/pnas.68.4.820", "pmcid": "PMC389051", "url": "https://pubmed.ncbi.nlm.nih.gov/5279523/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/5279523/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID5279523", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Original observations on 48 retinoblastoma cases and age/multiplicity statistics support a two-event model distinguishing inherited and sporadic disease.", "what_it_does_not_show": "Historical statistical inference does not directly identify the mutations or establish maintenance dependence; the inherited first event is not somatic.", "confounders_present": [ "Historical statistical inference does not directly identify the mutations or establish maintenance dependence; the inherited first event is not somatic." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 2, "pmid": "2841597", "title": "Genetic alterations during colorectal-tumor development.", "citation": "Vogelstein B, Fearon ER, Hamilton SR et al. Genetic alterations during colorectal-tumor development. The New England journal of medicine. 1988.", "doi": "10.1056/NEJM198809013190901", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/2841597/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/2841597/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID2841597", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Across 172 colorectal neoplasms, RAS mutation and chromosome losses accumulate with pathological progression.", "what_it_does_not_show": "Cross-sectional stages do not directly trace a single lineage or prove a universal obligatory order or ongoing dependency.", "confounders_present": [ "Cross-sectional stages do not directly trace a single lineage or prove a universal obligatory order or ongoing dependency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 3, "pmid": "25999502", "title": "Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.", "citation": "Martincorena I, Roshan A, Gerstung M et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science (New York, N.Y.). 2015.", "doi": "10.1126/science.aaa6806", "pmcid": "PMC4471149", "url": "https://pubmed.ncbi.nlm.nih.gov/25999502/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25999502/", "tier": "A", "source_tier": "A", "kind": "human_tissue", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25999502", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Deep sequencing of 234 normal skin biopsies from four people finds strong selection of cancer-associated genes while epidermal function is maintained.", "what_it_does_not_show": "Driver presence and competitive fitness are not equivalent to malignant sufficiency; benign clones do not refute later cooperative genetic causality.", "confounders_present": [ "Driver presence and competitive fitness are not equivalent to malignant sufficiency; benign clones do not refute later cooperative genetic causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 4, "pmid": "31645730", "title": "The landscape of somatic mutation in normal colorectal epithelial cells.", "citation": "Lee-Six H, Olafsson S, Ellis P et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature. 2019.", "doi": "10.1038/s41586-019-1672-7", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31645730/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31645730/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31645730", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Whole genomes from normal crypts of 42 individuals reveal mutational processes and probable drivers in around 1 percent of middle-aged crypts.", "what_it_does_not_show": "Normal mutant crypts are not inevitable precursors; acquisition alone does not establish cancer or maintenance.", "confounders_present": [ "Normal mutant crypts are not inevitable precursors; acquisition alone does not establish cancer or maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 5, "pmid": "29056346", "title": "Universal Patterns of Selection in Cancer and Somatic Tissues.", "citation": "Martincorena I, Raine KM, Gerstung M et al. Universal Patterns of Selection in Cancer and Somatic Tissues. Cell. 2017.", "doi": "10.1016/j.cell.2017.09.042", "pmcid": "PMC5720395", "url": "https://pubmed.ncbi.nlm.nih.gov/29056346/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29056346/", "tier": "A", "source_tier": "A", "kind": "human_tissue", "status_flags": [ "ErratumIn: PMID29906452" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID29056346", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Selection analysis of 7664 tumors across 29 types distinguishes positively selected coding variants and context-dependent driver burdens.", "what_it_does_not_show": "Statistical selection is not matched functional validation of every variant; coding substitution counts omit other genetic classes. Linked erratum metadata is retained.", "confounders_present": [ "Statistical selection is not matched functional validation of every variant; coding substitution counts omit other genetic classes. Linked erratum metadata is retained." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Pan-cancer public cohorts may overlap TCGA PMID24132290; computational reanalysis is not an independent clinical population." ] }, { "n": 6, "pmid": "31996850", "title": "Tobacco smoking and somatic mutations in human bronchial epithelium.", "citation": "Yoshida K, Gowers KHC, Lee-Six H et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature. 2020.", "doi": "10.1038/s41586-020-1961-1", "pmcid": "PMC7021511", "url": "https://pubmed.ncbi.nlm.nih.gov/31996850/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31996850/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31996850", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Whole genomes from 632 normal bronchial colonies link smoking to mutation burden and drivers; lower-burden cells are more frequent after cessation.", "what_it_does_not_show": "Sixteen subjects and normal-cell expansion do not directly estimate cancer prevention mediation; carcinogenic promotion can accompany mutagenesis.", "confounders_present": [ "Sixteen subjects and normal-cell expansion do not directly estimate cancer prevention mediation; carcinogenic promotion can accompany mutagenesis." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 7, "pmid": "31645765", "title": "Pan-cancer whole-genome analyses of metastatic solid tumours.", "citation": "Priestley P, Baber J, Lolkema MP et al. Pan-cancer whole-genome analyses of metastatic solid tumours. Nature. 2019.", "doi": "10.1038/s41586-019-1689-y", "pmcid": "PMC6872491", "url": "https://pubmed.ncbi.nlm.nih.gov/31645765/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31645765/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31645765", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "2520 metastatic tumor-normal genome pairs show predominantly clonal drivers, frequent genome duplication and biallelic suppressor inactivation.", "what_it_does_not_show": "Genomic prevalence and proposed actionability are not experimental necessity or successful treatment of each lesion.", "confounders_present": [ "Genomic prevalence and proposed actionability are not experimental necessity or successful treatment of each lesion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "29489755", "title": "Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours.", "citation": "Ma X, Liu Y, Liu Y et al. Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature. 2018.", "doi": "10.1038/nature25795", "pmcid": "PMC5854542", "url": "https://pubmed.ncbi.nlm.nih.gov/29489755/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29489755/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID29489755", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "1699 pediatric cancers reveal driver genes distinct from adult disease and a majority of alteration events as copy-number or structural changes.", "what_it_does_not_show": "Restricting mutation to point substitutions would misrepresent this genetic evidence; six histotypes do not establish pan-cancer primacy by perturbation.", "confounders_present": [ "Restricting mutation to point substitutions would misrepresent this genetic evidence; six histotypes do not establish pan-cancer primacy by perturbation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "24132290", "title": "Mutational landscape and significance across 12 major cancer types.", "citation": "Kandoth C, McLellan MD, Vandin F et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013.", "doi": "10.1038/nature12634", "pmcid": "PMC3927368", "url": "https://pubmed.ncbi.nlm.nih.gov/24132290/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24132290/", "tier": "A", "source_tier": "A", "kind": "human_tissue", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24132290", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "TCGA analysis of 3281 tumors across 12 types identifies significantly mutated genes, pathways and inferred clonal timing.", "what_it_does_not_show": "Significance and survival associations cannot establish every alteration as functional or define an obligatory cancer sequence.", "confounders_present": [ "Significance and survival associations cannot establish every alteration as functional or define an obligatory cancer sequence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 10, "pmid": "41062696", "title": "Somatic mutation and selection at population scale.", "citation": "Lawson ARJ, Abascal F, Nicola PA et al. Somatic mutation and selection at population scale. Nature. 2025.", "doi": "10.1038/s41586-025-09584-w", "pmcid": "PMC12611758", "url": "https://pubmed.ncbi.nlm.nih.gov/41062696/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41062696/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID41062696", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "NanoSeq profiles 1042 oral and 371 blood samples, detecting many selected clones with high sequencing specificity.", "what_it_does_not_show": "Population-scale clonal fitness is not malignant sufficiency or progression necessity; these normal tissues are not independent cancer interventions.", "confounders_present": [ "Population-scale clonal fitness is not malignant sufficiency or progression necessity; these normal tissues are not independent cancer interventions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 11, "pmid": "39492056", "title": "Genomes and epigenomes of matched normal and tumor breast tissue reveal diverse evolutionary trajectories and tumor-host interactions.", "citation": "Zhu B, Tapinos A, Koka H et al. Genomes and epigenomes of matched normal and tumor breast tissue reveal diverse evolutionary trajectories and tumor-host interactions. American journal of human genetics. 2024.", "doi": "10.1016/j.ajhg.2024.10.005", "pmcid": "PMC11639081", "url": "https://pubmed.ncbi.nlm.nih.gov/39492056/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39492056/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39492056", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Matched normal-adjacent and breast-tumor genome/epigenome profiles from 43 people reveal shared and divergent evolutionary histories.", "what_it_does_not_show": "Adjacent tissue and inferred phylogenies cannot alone prove nongenetic initiation or distinguish all tumor-host directions.", "confounders_present": [ "Adjacent tissue and inferred phylogenies cannot alone prove nongenetic initiation or distinguish all tumor-host directions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 12, "pmid": "30337457", "title": "Somatic mutant clones colonize the human esophagus with age.", "citation": "Martincorena I, Fowler JC, Wabik A et al. Somatic mutant clones colonize the human esophagus with age. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aau3879", "pmcid": "PMC6298579", "url": "https://pubmed.ncbi.nlm.nih.gov/30337457/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30337457/", "tier": "A", "source_tier": "A", "kind": "human_tissue", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30337457", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Detection of mutations in normal esophagus, 2:Colonization of the epithelium by NOTCH1-mutant clones. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Normal esophagus has abundant positively selected NOTCH1 and TP53 clones; NOTCH1 alterations are more prevalent in normal tissue than cancer.", "what_it_does_not_show": "Original sections distinguish approximate allele-fraction-derived cell coverage from independent mutations, and contrast TP53 enrichment in tumors. Normal fitness does not negate genotype-specific cancer dependencies.", "confounders_present": [ "Original sections distinguish approximate allele-fraction-derived cell coverage from independent mutations, and contrast TP53 enrichment in tumors. Normal fitness does not negate genotype-specific cancer dependencies." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 13, "pmid": "30602793", "title": "Age-related remodelling of oesophageal epithelia by mutated cancer drivers.", "citation": "Yokoyama A, Kakiuchi N, Yoshizato T et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature. 2019.", "doi": "10.1038/s41586-018-0811-x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30602793/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30602793/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30602793", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "682 normal esophageal samples show age/lifestyle-associated expansion and overrepresentation of some driver genes relative to cancer.", "what_it_does_not_show": "Cross-sectional remodelling is not direct malignant-lineage tracking; gene-specific fitness differs between normal and cancer tissue.", "confounders_present": [ "Cross-sectional remodelling is not direct malignant-lineage tracking; gene-specific fitness differs between normal and cancer tissue." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "35650444", "title": "The longitudinal dynamics and natural history of clonal haematopoiesis.", "citation": "Fabre MA, de Almeida JG, Fiorillo E et al. The longitudinal dynamics and natural history of clonal haematopoiesis. Nature. 2022.", "doi": "10.1038/s41586-022-04785-z", "pmcid": "PMC9177423", "url": "https://pubmed.ncbi.nlm.nih.gov/35650444/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35650444/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35650444", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Longitudinal tracking of 697 hematopoietic clones in 385 people links genotype-specific growth and malignant progression risk.", "what_it_does_not_show": "Risk enrichment and growth are not deterministic malignancy; age and competitive context condition the same mutation.", "confounders_present": [ "Risk enrichment and growth are not deterministic malignancy; age and competitive context condition the same mutation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 15, "pmid": "34646013", "title": "Mutant clones in normal epithelium outcompete and eliminate emerging tumours.", "citation": "Colom B, Herms A, Hall MWJ et al. Mutant clones in normal epithelium outcompete and eliminate emerging tumours. Nature. 2021.", "doi": "10.1038/s41586-021-03965-7", "pmcid": "PMC7612642", "url": "https://pubmed.ncbi.nlm.nih.gov/34646013/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34646013/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34646013", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Endogenous mouse esophageal carcinogenesis and competitive-clone induction/inhibition show mutant neighboring epithelium can eliminate nascent tumors.", "what_it_does_not_show": "Competition is a causal tissue modifier with retained mutant neoplasms, not proof that genetic lesions are dispensable across cancer.", "confounders_present": [ "Competition is a causal tissue modifier with retained mutant neoplasms, not proof that genetic lesions are dispensable across cancer." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 16, "pmid": "35177608", "title": "Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium.", "citation": "Yamaguchi M, Nakaoka H, Suda K et al. Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium. Nature communications. 2022.", "doi": "10.1038/s41467-022-28568-2", "pmcid": "PMC8854701", "url": "https://pubmed.ncbi.nlm.nih.gov/35177608/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35177608/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35177608", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "1311 normal endometrial glands reveal rhizome-linked clonal expansion and early copy-neutral loss of heterozygosity persisting in normal tissue.", "what_it_does_not_show": "Clonal architecture and tolerated alterations are not cancer sufficiency; mutations include structural/allelic events beyond point substitutions.", "confounders_present": [ "Clonal architecture and tolerated alterations are not cancer sufficiency; mutations include structural/allelic events beyond point substitutions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 17, "pmid": "34433965", "title": "A body map of somatic mutagenesis in morphologically normal human tissues.", "citation": "Li R, Di L, Li J et al. A body map of somatic mutagenesis in morphologically normal human tissues. Nature. 2021.", "doi": "10.1038/s41586-021-03836-1", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34433965/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34433965/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34433965", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "1737 normal biopsies across nine organs from five donors show tissue-dependent mutational accumulation and clonal architecture.", "what_it_does_not_show": "Spatial restriction and morphology do not exclude occult precursor states or establish a genetic-versus-tissue causal hierarchy.", "confounders_present": [ "Spatial restriction and morphology do not exclude occult precursor states or establish a genetic-versus-tissue causal hierarchy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 18, "pmid": "32350471", "title": "The mutational landscape of normal human endometrial epithelium.", "citation": "Moore L, Leongamornlert D, Coorens THH et al. The mutational landscape of normal human endometrial epithelium. Nature. 2020.", "doi": "10.1038/s41586-020-2214-z", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32350471/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32350471/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32350471", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Normal endometrial genomes contain driver-bearing clones acquired early and expanded with age, with lower burdens than cancers.", "what_it_does_not_show": "Many normal driver-bearing glands never become malignant; driver presence alone is insufficient but can precede cooperative cancer evolution.", "confounders_present": [ "Many normal driver-bearing glands never become malignant; driver presence alone is insufficient but can precede cooperative cancer evolution." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 19, "pmid": "9054499", "title": "Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.", "citation": "Serrano M, Lin AW, McCurrach ME et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997.", "doi": "10.1016/s0092-8674(00)81902-9", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9054499/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9054499/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID9054499", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Oncogenic RAS induces arrest in primary cells; p53/p16 inactivation or E1A permits bypass in defined species and cell systems.", "what_it_does_not_show": "Forced expression and cell culture establish a cooperative checkpoint, not endogenous pan-cancer necessity or a universal mutation sequence.", "confounders_present": [ "Forced expression and cell culture establish a cooperative checkpoint, not endogenous pan-cancer necessity or a universal mutation sequence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 20, "pmid": "37828026", "title": "Oncogenic context shapes the fitness landscape of tumor suppression.", "citation": "Blair LM, Juan JM, Sebastian L et al. Oncogenic context shapes the fitness landscape of tumor suppression. Nature communications. 2023.", "doi": "10.1038/s41467-023-42156-y", "pmcid": "PMC10570323", "url": "https://pubmed.ncbi.nlm.nih.gov/37828026/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37828026/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37828026", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph3, 1:Results:paragraph4, 1:Results:paragraph18, 1:Results:paragraph19, 1:Results:paragraph20, 1:Results:paragraph21, 1:Results:paragraph24, 1:Results:paragraph28. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "what_it_does_not_show": "Original Results include inert-cutting and Cas9-negative controls and separate clone number from growth. Four lung contexts do not represent all histologies; mutation frequency alone predicts some functional effects poorly.", "confounders_present": [ "Original Results include inert-cutting and Cas9-negative controls and separate clone number from growth. Four lung contexts do not represent all histologies; mutation frequency alone predicts some functional effects poorly." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "34079124", "title": "NOTUM from Apc-mutant cells biases clonal competition to initiate cancer.", "citation": "Flanagan DJ, Pentinmikko N, Luopajärvi K et al. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature. 2021.", "doi": "10.1038/s41586-021-03525-z", "pmcid": "PMC7615049", "url": "https://pubmed.ncbi.nlm.nih.gov/34079124/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34079124/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34079124", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Apc-mutant cells secrete NOTUM; genetic or pharmacological inhibition reduces wild-type competition loss, mutant fixation and adenomas.", "what_it_does_not_show": "This is genetic causality mediated through the niche, not a competing mutation-free account; prevention of adenomas is not universal invasive-cancer maintenance.", "confounders_present": [ "This is genetic causality mediated through the niche, not a competing mutation-free account; prevention of adenomas is not universal invasive-cancer maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 22, "pmid": "17251932", "title": "Restoration of p53 function leads to tumour regression in vivo.", "citation": "Ventura A, Kirsch DG, McLaughlin ME et al. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007.", "doi": "10.1038/nature05541", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17251932/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17251932/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID17251932", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Restoring endogenous p53 regresses autochthonous lymphomas and sarcomas with different apoptosis/senescence responses and no detected normal-tissue injury.", "what_it_does_not_show": "Defined p53-dependent models establish maintenance causality; they do not show every tumor is dependent or replace initiation with maintenance. Original body unavailable here.", "confounders_present": [ "Defined p53-dependent models establish maintenance causality; they do not show every tumor is dependent or replace initiation with maintenance. Original body unavailable here." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 23, "pmid": "15894267", "title": "Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.", "citation": "Hingorani SR, Wang L, Multani AS et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer cell. 2005.", "doi": "10.1016/j.ccr.2005.04.023", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15894267/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15894267/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID15894267", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Endogenous Kras G12D and Trp53 R172H cooperate to generate invasive, metastatic pancreatic cancer with genomic instability.", "what_it_does_not_show": "Prespecified engineered alleles show joint sufficiency in this tissue, not a universal sequence or mutation-only explanation of tissue context.", "confounders_present": [ "Prespecified engineered alleles show joint sufficiency in this tissue, not a universal sequence or mutation-only explanation of tissue context." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 24, "pmid": "14706336", "title": "Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.", "citation": "Hingorani SR, Petricoin EF, Maitra A et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer cell. 2003.", "doi": "10.1016/s1535-6108(03)00309-x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/14706336/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/14706336/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID14706336", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Physiological mutant Kras expression induces the PanIN spectrum, with low-frequency spontaneous invasive/metastatic progression.", "what_it_does_not_show": "Initiation is genetically imposed and pancreatic-lineage-specific; additional evolution and microenvironmental conditions remain.", "confounders_present": [ "Initiation is genetically imposed and pancreatic-lineage-specific; additional evolution and microenvironmental conditions remain." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 25, "pmid": "11751630", "title": "Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras.", "citation": "Jackson EL, Willis N, Mercer K et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes & development. 2001.", "doi": "10.1101/gad.943001", "pmcid": "PMC312845", "url": "https://pubmed.ncbi.nlm.nih.gov/11751630/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11751630/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID11751630", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Conditional endogenous oncogenic Kras permits timed autochthonous lung tumor induction and progression analysis.", "what_it_does_not_show": "Cre induction supplies the initiating alteration; no mutation-loss maintenance test or broad histological generalization follows from this report alone.", "confounders_present": [ "Cre induction supplies the initiating alteration; no mutation-loss maintenance test or broad histological generalization follows from this report alone." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 26, "pmid": "23226501", "title": "Metastatic pancreatic cancer is dependent on oncogenic Kras in mice.", "citation": "Collins MA, Brisset JC, Zhang Y et al. Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. PloS one. 2012.", "doi": "10.1371/journal.pone.0049707", "pmcid": "PMC3513322", "url": "https://pubmed.ncbi.nlm.nih.gov/23226501/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23226501/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "inducible-pancreatic-Kras-platform", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph19, 1:Results:paragraph20, 1:Results:paragraph22, 1:Results:paragraph24, 1:Results:paragraph26, 1:Results:paragraph29. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Inducible pancreatic Kras withdrawal regresses primary and metastatic tumors; reactivation rapidly restores disease.", "what_it_does_not_show": "Original Results show TetO-Kras with endogenous mutant p53 and induced pancreatitis. Off-doxy relapse occurs after culture/transplantation, not in the autochthonous mice; do not conflate those arms or call Kras endogenous expression.", "confounders_present": [ "Original Results show TetO-Kras with endogenous mutant p53 and induced pancreatitis. Off-doxy relapse occurs after culture/transplantation, not in the autochthonous mice; do not conflate those arms or call Kras endogenous expression." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Related inducible Kras platform and team to PMID22232209, with added mutant p53/metastasis analysis." ] }, { "n": 27, "pmid": "14966562", "title": "Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease.", "citation": "Chan IT, Kutok JL, Williams IR et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. The Journal of clinical investigation. 2004.", "doi": "10.1172/JCI20476", "pmcid": "PMC338267", "url": "https://pubmed.ncbi.nlm.nih.gov/14966562/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/14966562/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID14966562", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Conditional oncogenic Kras from its endogenous promoter causes fully penetrant myeloproliferation but not transplantable AML.", "what_it_does_not_show": "A disease precursor dependency is not AML sufficiency, supporting genetic cooperation and lineage boundaries.", "confounders_present": [ "A disease precursor dependency is not AML sufficiency, supporting genetic cooperation and lineage boundaries." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 28, "pmid": "22232209", "title": "Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice.", "citation": "Collins MA, Bednar F, Zhang Y et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. The Journal of clinical investigation. 2012.", "doi": "10.1172/JCI59227", "pmcid": "PMC3266788", "url": "https://pubmed.ncbi.nlm.nih.gov/22232209/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22232209/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "inducible-pancreatic-Kras-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Reversible pancreas-specific Kras expression induces and maintains lesions, with withdrawal causing regression and changes in fibroinflammatory stroma.", "what_it_does_not_show": "Transgenic activation and tissue damage condition initiation; stromal mediation can be downstream of a causal mutation rather than an exclusive alternative.", "confounders_present": [ "Transgenic activation and tissue damage condition initiation; stromal mediation can be downstream of a causal mutation rather than an exclusive alternative." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 29, "pmid": "10488335", "title": "Reversible tumorigenesis by MYC in hematopoietic lineages.", "citation": "Felsher DW, Bishop JM et al. Reversible tumorigenesis by MYC in hematopoietic lineages. Molecular cell. 1999.", "doi": "10.1016/s1097-2765(00)80367-6", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10488335/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10488335/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID10488335", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Conditional MYC expression produces hematologic malignancies that regress after transgene inactivation, with differentiation and restored hematopoiesis.", "what_it_does_not_show": "Forced oncogene expression without endogenous mutation correction narrows interpretation to the induced dependency.", "confounders_present": [ "Forced oncogene expression without endogenous mutation correction narrows interpretation to the induced dependency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 30, "pmid": "15475948", "title": "MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.", "citation": "Shachaf CM, Kopelman AM, Arvanitis C et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004.", "doi": "10.1038/nature03043", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15475948/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15475948/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID15475948", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "MYC-off liver tumors differentiate and become dormant; reactivation restores malignancy with the same comparative-genomic signature.", "what_it_does_not_show": "Reversal changes driver activity rather than eliminating every mutation; latent tumor identity and tissue-specific responses constrain permanent cure claims.", "confounders_present": [ "Reversal changes driver activity rather than eliminating every mutation; latent tumor identity and tissue-specific responses constrain permanent cure claims." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 31, "pmid": "23467612", "title": "Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer.", "citation": "Lin WC, Rajbhandari N, Liu C et al. Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer. Cancer research. 2013.", "doi": "10.1158/0008-5472.CAN-12-2067", "pmcid": "PMC3602120", "url": "https://pubmed.ncbi.nlm.nih.gov/23467612/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23467612/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID23467612", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Inducible pancreatic MYC tumors regress after inactivation but residual cells rapidly recur on re-expression.", "what_it_does_not_show": "Marker-positive residual cells are not proof of a universal stem hierarchy; transgene-driven maintenance does not establish natural mutation primacy.", "confounders_present": [ "Marker-positive residual cells are not proof of a universal stem hierarchy; transgene-driven maintenance does not establish natural mutation primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 32, "pmid": "12098700", "title": "Sustained loss of a neoplastic phenotype by brief inactivation of MYC.", "citation": "Jain M, Arvanitis C, Chu K et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science (New York, N.Y.). 2002.", "doi": "10.1126/science.1071489", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12098700/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12098700/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID12098700", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Brief MYC inactivation produces sustained osteogenic tumor regression; reactivation induces apoptosis instead of recurrence.", "what_it_does_not_show": "Tissue-specific epigenetic memory modifies response to the same driver; induced expression and inferred epigenetic mechanism limit universal conclusions.", "confounders_present": [ "Tissue-specific epigenetic memory modifies response to the same driver; induced expression and inferred epigenetic mechanism limit universal conclusions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "21035406", "title": "CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation.", "citation": "Rakhra K, Bachireddy P, Zabuawala T et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer cell. 2010.", "doi": "10.1016/j.ccr.2010.10.002", "pmcid": "PMC2991103", "url": "https://pubmed.ncbi.nlm.nih.gov/21035406/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21035406/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21035406", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "CD4 and thrombospondin functional contrasts show immune remodelling is required for sustained regression after MYC/BCR-ABL inactivation.", "what_it_does_not_show": "Oncogene withdrawal and immune context cooperate; immune necessity does not negate genetic dependence. Linked erratum lacks a supplied PMID and details remain unexamined.", "confounders_present": [ "Oncogene withdrawal and immune context cooperate; immune necessity does not negate genetic dependence. Linked erratum lacks a supplied PMID and details remain unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 34, "pmid": "25924068", "title": "Sequential cancer mutations in cultured human intestinal stem cells.", "citation": "Drost J, van Jaarsveld RH, Ponsioen B et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature. 2015.", "doi": "10.1038/nature14415", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25924068/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25924068/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25924068", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "organoid", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "what_it_does_not_show": "Culture selection and xenotransplantation alone do not establish endogenous human cancer dependency; engineered order is not proof of obligatory order.", "confounders_present": [ "Culture selection and xenotransplantation alone do not establish endogenous human cancer dependency; engineered order is not proof of obligatory order." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Engineered organoid/niche selection approach related to later organoid reports." ] }, { "n": 35, "pmid": "25706875", "title": "Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids.", "citation": "Matano M, Date S, Shimokawa M et al. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nature medicine. 2015.", "doi": "10.1038/nm.3802", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25706875/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25706875/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25706875", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "organoid", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "what_it_does_not_show": "Driver edits support causal sufficiency in the tested niche; invasion/metastasis requires additional lesions or context and is not fully reproduced.", "confounders_present": [ "Driver edits support causal sufficiency in the tested niche; invasion/metastasis requires additional lesions or context and is not fully reproduced." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 36, "pmid": "28270604", "title": "Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids.", "citation": "Fumagalli A, Drost J, Suijkerbuijk SJ et al. Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. Proceedings of the National Academy of Sciences of the United States of America. 2017.", "doi": "10.1073/pnas.1701219114", "pmcid": "PMC5373343", "url": "https://pubmed.ncbi.nlm.nih.gov/28270604/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28270604/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28270604", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "organoid", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Orthotopic engineered organoids show mutation accumulation supports metastasis; specific niche signals restore growth when one oncogenic alteration is absent.", "what_it_does_not_show": "Transplantation and niche rescue are bounded model evidence, not proof of mutation dispensability in all spontaneous cancers.", "confounders_present": [ "Transplantation and niche rescue are bounded model evidence, not proof of mutation dispensability in all spontaneous cancers." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 37, "pmid": "39487295", "title": "Recapitulating the adenoma-carcinoma sequence by selection of four spontaneous oncogenic mutations in mismatch-repair-deficient human colon organoids.", "citation": "Mizutani T, Boretto M, Lim S et al. Recapitulating the adenoma-carcinoma sequence by selection of four spontaneous oncogenic mutations in mismatch-repair-deficient human colon organoids. Nature cancer. 2024.", "doi": "10.1038/s43018-024-00841-x", "pmcid": "PMC11663794", "url": "https://pubmed.ncbi.nlm.nih.gov/39487295/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39487295/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39487295", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "organoid", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "what_it_does_not_show": "Repair-defective background and designed selection are not ordinary in vivo initiation; spontaneous acquisition does not remove culture/transplant limits.", "confounders_present": [ "Repair-defective background and designed selection are not ordinary in vivo initiation; spontaneous acquisition does not remove culture/transplant limits." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Different spontaneous mutations but shared repair-defective organoid and culture/transplant assay class." ] }, { "n": 38, "pmid": "37017636", "title": "Oncogenic signaling is coupled to colorectal cancer cell differentiation state.", "citation": "Sell T, Klotz C, Fischer MM et al. Oncogenic signaling is coupled to colorectal cancer cell differentiation state. The Journal of cell biology. 2023.", "doi": "10.1083/jcb.202204001", "pmcid": "PMC10082329", "url": "https://pubmed.ncbi.nlm.nih.gov/37017636/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37017636/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37017636", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "organoid", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Isogenic and patient-derived colorectal organoids link driver combinations to differentiation-dependent signaling and transcription.", "what_it_does_not_show": "Single-cell maps and state associations do not isolate organismal necessity; differentiation coupling can coexist with genetic causality.", "confounders_present": [ "Single-cell maps and state associations do not isolate organismal necessity; differentiation coupling can coexist with genetic causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 39, "pmid": "26091037", "title": "Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer.", "citation": "Dow LE, O'Rourke KP, Simon J et al. Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer. Cell. 2015.", "doi": "10.1016/j.cell.2015.05.033", "pmcid": "PMC4475279", "url": "https://pubmed.ncbi.nlm.nih.gov/26091037/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26091037/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26091037", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph13, 1:Results:paragraph14, 1:Results:paragraph15, 1:Results:paragraph16. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Endogenous APC protein restoration reverses autochthonous colorectal adenomas/carcinomas, including Kras/p53-altered settings, with lineage-marked normal crypt behavior.", "what_it_does_not_show": "Original Results show reversible shRNA loss rather than precise mutation repair, small Kras/p53 groups, residual microadenomas and repeat regrowth on APC re-silencing; this is powerful defined dependency, not permanent eradication of all mutant cells.", "confounders_present": [ "Original Results show reversible shRNA loss rather than precise mutation repair, small Kras/p53 groups, residual microadenomas and repeat regrowth on APC re-silencing; this is powerful defined dependency, not permanent eradication of all mutant cells." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 40, "pmid": "38658752", "title": "Transient loss of Polycomb components induces an epigenetic cancer fate.", "citation": "Parreno V, Loubiere V, Schuettengruber B et al. Transient loss of Polycomb components induces an epigenetic cancer fate. Nature. 2024.", "doi": "10.1038/s41586-024-07328-w", "pmcid": "PMC11096130", "url": "https://pubmed.ncbi.nlm.nih.gov/38658752/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38658752/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38658752", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Epigenetic perturbations initiate tumours:paragraph0, 1:Epigenetic perturbations initiate tumours:paragraph2, 1:Epigenetic perturbations initiate tumours:paragraph3, 1:Epigenetic perturbations initiate tumours:paragraph4, 1:Epigenetic perturbations initiate tumours:paragraph5, 6:EICs are autonomous immortal tumours:paragraph0, 6:EICs are autonomous immortal tumours:paragraph1, 8:Methods:paragraph19, 8:Methods:paragraph29, 8:Methods:paragraph30. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Transient endogenous Polycomb depletion induces persistent native fly neoplasia after protein recovery; serial allografts grow and metastasize.", "what_it_does_not_show": "Original Results/Methods test four controls and 12 tumors with pooled whole-genome data, no recurrent drivers and variant/allele-fraction thresholds. This does not prove zero sequence changes or ordinary human mutation-free prevalence; transplantation is not its only initiation evidence.", "confounders_present": [ "Original Results/Methods test four controls and 12 tumors with pooled whole-genome data, no recurrent drivers and variant/allele-fraction thresholds. This does not prove zero sequence changes or ordinary human mutation-free prevalence; transplantation is not its only initiation evidence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 41, "pmid": "16169468", "title": "Tensional homeostasis and the malignant phenotype.", "citation": "Paszek MJ, Zahir N, Johnson KR et al. Tensional homeostasis and the malignant phenotype. Cancer cell. 2005.", "doi": "10.1016/j.ccr.2005.08.010", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16169468/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16169468/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID16169468", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Matrix stiffness, integrin/Rho/ERK manipulations and contractility reduction alter malignant architecture in an integrated signaling circuit.", "what_it_does_not_show": "In vitro phenotype reversion is not pan-cancer initiation or survival causality and does not remove the transformed genotype.", "confounders_present": [ "In vitro phenotype reversion is not pan-cancer initiation or survival causality and does not remove the transformed genotype." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 42, "pmid": "24856586", "title": "Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.", "citation": "Özdemir BC, Pentcheva-Hoang T, Carstens JL et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer cell. 2014.", "doi": "10.1016/j.ccr.2014.04.005", "pmcid": "PMC4180632", "url": "https://pubmed.ncbi.nlm.nih.gov/24856586/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24856586/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24856586", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Genetic depletion of proliferating alphaSMA fibroblasts accelerates pancreatic cancer and worsens survival; anti-CTLA4 partially rescues the altered state.", "what_it_does_not_show": "Original Results replicate genetic backgrounds and retain poorer survival despite lower tumor weight, with pulmonary emboli and immune changes; stroma can restrain rather than uniformly promote cancer.", "confounders_present": [ "Original Results replicate genetic backgrounds and retain poorer survival despite lower tumor weight, with pulmonary emboli and immune changes; stroma can restrain rather than uniformly promote cancer." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 43, "pmid": "16251424", "title": "Stromal regulation of neoplastic development: age-dependent normalization of neoplastic mammary cells by mammary stroma.", "citation": "Maffini MV, Calabro JM, Soto AM et al. Stromal regulation of neoplastic development: age-dependent normalization of neoplastic mammary cells by mammary stroma. The American journal of pathology. 2005.", "doi": "10.1016/S0002-9440(10)61227-8", "pmcid": "PMC1603788", "url": "https://pubmed.ncbi.nlm.nih.gov/16251424/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16251424/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID16251424", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Rat mammary stroma age/parity changes tumor incidence and permits normal ducts containing a tumor-origin RAS marker.", "what_it_does_not_show": "Transplantation and host developmental/reproductive differences do not establish a universal tissue-first origin; persistent RAS marker supports genotype–phenotype separation.", "confounders_present": [ "Transplantation and host developmental/reproductive differences do not establish a universal tissue-first origin; persistent RAS marker supports genotype–phenotype separation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 44, "pmid": "29560858", "title": "Transient external force induces phenotypic reversion of malignant epithelial structures via nitric oxide signaling.", "citation": "Ricca BL, Venugopalan G, Furuta S et al. Transient external force induces phenotypic reversion of malignant epithelial structures via nitric oxide signaling. eLife. 2018.", "doi": "10.7554/eLife.26161", "pmcid": "PMC5862525", "url": "https://pubmed.ncbi.nlm.nih.gov/29560858/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29560858/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID29560858", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Brief compression induces normal-like malignant breast structures; nitric-oxide inhibition blocks the architectural response.", "what_it_does_not_show": "Three-dimensional morphology is not verified spontaneous cancer elimination or survival; altered context does not erase genomic lesions.", "confounders_present": [ "Three-dimensional morphology is not verified spontaneous cancer elimination or survival; altered context does not erase genomic lesions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 45, "pmid": "9105051", "title": "Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies.", "citation": "Weaver VM, Petersen OW, Wang F et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. The Journal of cell biology. 1997.", "doi": "10.1083/jcb.137.1.231", "pmcid": "PMC2139858", "url": "https://pubmed.ncbi.nlm.nih.gov/9105051/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9105051/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID9105051", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Beta1-integrin inhibitory antibody/Fab reverses malignant breast architecture and reduces nude-mouse tumor formation; stimulatory antibody fails.", "what_it_does_not_show": "Reversion is reversible on antibody removal; transplant/culture evidence supports contextual phenotype control but not tissue primacy across endogenous cancers.", "confounders_present": [ "Reversion is reversible on antibody removal; transplant/culture evidence supports contextual phenotype control but not tissue primacy across endogenous cancers." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 46, "pmid": "37020004", "title": "Lung adenocarcinoma promotion by air pollutants.", "citation": "Hill W, Lim EL, Weeden CE et al. Lung adenocarcinoma promotion by air pollutants. Nature. 2023.", "doi": "10.1038/s41586-023-05874-3", "pmcid": "PMC7614604", "url": "https://pubmed.ncbi.nlm.nih.gov/37020004/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37020004/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37020004", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:PM-mediated promotion of lung cancer:paragraph0, 1:PM-mediated promotion of lung cancer:paragraph1, 3:PM induces IL-1β production from macrophages. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "PM2.5 promotes EGFR/KRAS-mutant lung lesions; macrophage/IL1beta experiments connect inflammatory promotion to altered epithelial state.", "what_it_does_not_show": "Original Results show pre-existing engineered drivers, short-term PM-versus-PBS genome comparisons and concomitant antibody suppression. This is nonmutagenic promotion in a mutant substrate, not proof that mutations are unnecessary.", "confounders_present": [ "Original Results show pre-existing engineered drivers, short-term PM-versus-PBS genome comparisons and concomitant antibody suppression. This is nonmutagenic promotion in a mutant substrate, not proof that mutations are unnecessary." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 47, "pmid": "14996910", "title": "The stroma as a crucial target in rat mammary gland carcinogenesis.", "citation": "Maffini MV, Soto AM, Calabro JM et al. The stroma as a crucial target in rat mammary gland carcinogenesis. Journal of cell science. 2004.", "doi": "10.1242/jcs.01000", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/14996910/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/14996910/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID14996910", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Rat recombination contrasts place NMU-associated mammary tumor initiation with exposed stroma, independent of epithelial exposure; Ha-ras status does not track all tumors.", "what_it_does_not_show": "Different compartment exposure protocols, transplantation and one-gene mutation testing do not establish absence of other drivers or pan-cancer tissue-first necessity.", "confounders_present": [ "Different compartment exposure protocols, transplantation and one-gene mutation testing do not establish absence of other drivers or pan-cancer tissue-first necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "17189715", "title": "Mad2 overexpression promotes aneuploidy and tumorigenesis in mice.", "citation": "Sotillo R, Hernando E, Díaz-Rodríguez E et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer cell. 2007.", "doi": "10.1016/j.ccr.2006.10.019", "pmcid": "PMC1850996", "url": "https://pubmed.ncbi.nlm.nih.gov/17189715/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17189715/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID17189715", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Transient Mad2 overexpression induces chromosome instability and multiple tumor types; sustained Mad2 is unnecessary for maintenance.", "what_it_does_not_show": "Chromosome gains/losses are genetic alterations; forced checkpoint expression is not an endogenous mutation-free origin or universal CIN-first model.", "confounders_present": [ "Chromosome gains/losses are genetic alterations; forced checkpoint expression is not an endogenous mutation-free origin or universal CIN-first model." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 49, "pmid": "20173739", "title": "Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal.", "citation": "Sotillo R, Schvartzman JM, Socci ND et al. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature. 2010.", "doi": "10.1038/nature08803", "pmcid": "PMC2841716", "url": "https://pubmed.ncbi.nlm.nih.gov/20173739/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20173739/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID20173739", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Mad2-mediated chromosome instability increases Kras-independent relapse after initial regression on oncogene withdrawal.", "what_it_does_not_show": "Engineered chromosome instability and varied relapse pathways support a context, not all cancers or absence of genetic evolution.", "confounders_present": [ "Engineered chromosome instability and varied relapse pathways support a context, not all cancers or absence of genetic evolution." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 50, "pmid": "1059147", "title": "Normal genetically mosaic mice produced from malignant teratocarcinoma cells.", "citation": "Mintz B, Illmensee K et al. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proceedings of the National Academy of Sciences of the United States of America. 1975.", "doi": "10.1073/pnas.72.9.3585", "pmcid": "PMC433040", "url": "https://pubmed.ncbi.nlm.nih.gov/1059147/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/1059147/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID1059147", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Malignant teratocarcinoma cells contribute to functional normal tissues and germline after blastocyst incorporation.", "what_it_does_not_show": "Modal chromosome number and strain markers are not modern genome-wide driver exclusion; rare embryonic reprogramming cannot estimate ordinary adult cancer prevalence.", "confounders_present": [ "Modal chromosome number and strain markers are not modern genome-wide driver exclusion; rare embryonic reprogramming cannot estimate ordinary adult cancer prevalence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Historical modal chromosome/strain markers are not a modern genome-wide exclusion of mutations." ] }, { "n": 51, "pmid": "24529372", "title": "Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation.", "citation": "Ohnishi K, Semi K, Yamamoto T et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell. 2014.", "doi": "10.1016/j.cell.2014.01.005", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24529372/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24529372/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24529372", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Interrupted in vivo reprogramming induces dysplastic tumors, and tumor-derived iPSCs can form nonneoplastic kidney cells.", "what_it_does_not_show": "Forced reprogramming and developmental reset demonstrate context-specific epigenetic plasticity; reversibility is not sensitive genome-wide proof of zero mutations or broad human predominance.", "confounders_present": [ "Forced reprogramming and developmental reset demonstrate context-specific epigenetic plasticity; reversibility is not sensitive genome-wide proof of zero mutations or broad human predominance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "26700815", "title": "Insulator dysfunction and oncogene activation in IDH mutant gliomas.", "citation": "Flavahan WA, Drier Y, Liau BB et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016.", "doi": "10.1038/nature16490", "pmcid": "PMC4831574", "url": "https://pubmed.ncbi.nlm.nih.gov/26700815/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26700815/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26700815", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "what_it_does_not_show": "Mutation-to-epigenetic causation is an integrated mechanism, not an independent refutation of mutations. Gliomasphere proliferation is not complete in vivo cancer dependency.", "confounders_present": [ "Mutation-to-epigenetic causation is an integrated mechanism, not an independent refutation of mutations. Gliomasphere proliferation is not complete in vivo cancer dependency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "28607484", "title": "Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance.", "citation": "Shaffer SM, Dunagin MC, Torborg SR et al. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature. 2017.", "doi": "10.1038/nature22794", "pmcid": "PMC5542814", "url": "https://pubmed.ncbi.nlm.nih.gov/28607484/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28607484/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID29466340" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28607484", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Rare melanoma transcriptional states predict resistance and drug-induced reprogramming stabilizes it.", "what_it_does_not_show": "Resistance-state plasticity does not establish nongenetic original initiation; no clear genetic cause is not exhaustive exclusion. Linked correction details are qualified.", "confounders_present": [ "Resistance-state plasticity does not establish nongenetic original initiation; no clear genetic cause is not exhaustive exclusion. Linked correction details are qualified." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "20371346", "title": "A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.", "citation": "Sharma SV, Lee DY, Li B et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010.", "doi": "10.1016/j.cell.2010.02.027", "pmcid": "PMC2851638", "url": "https://pubmed.ncbi.nlm.nih.gov/20371346/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20371346/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID20371346", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Single-clone cancer cultures yield reversible persisters; KDM5A depletion reduces tolerance without detectable parental proliferation loss.", "what_it_does_not_show": "Original Results distinguish nine-doubling persister reversal from roughly 90-doubling expanded-persistor reversal and CD133/quiescence controls. These cells retain cancer-driving mutations; clinical relapse necessity is not directly tested.", "confounders_present": [ "Original Results distinguish nine-doubling persister reversal from roughly 90-doubling expanded-persistor reversal and CD133/quiescence controls. These cells retain cancer-driving mutations; clinical relapse necessity is not directly tested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 55, "pmid": "37407818", "title": "Therapy-induced APOBEC3A drives evolution of persistent cancer cells.", "citation": "Isozaki H, Sakhtemani R, Abbasi A et al. Therapy-induced APOBEC3A drives evolution of persistent cancer cells. Nature. 2023.", "doi": "10.1038/s41586-023-06303-1", "pmcid": "PMC10804446", "url": "https://pubmed.ncbi.nlm.nih.gov/37407818/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37407818/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37407818", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Therapy induces APOBEC3A in persisters; deletion reduces mutations/structural changes and delays resistance, with concordant patient signatures.", "what_it_does_not_show": "Genetic evolution can arise from a nongenetic persister state; patient signatures and cell models do not prove every resistance lineage follows this route.", "confounders_present": [ "Genetic evolution can arise from a nongenetic persister state; patient signatures and cell models do not prove every resistance lineage follows this route." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "26828195", "title": "Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.", "citation": "Hata AN, Niederst MJ, Archibald HL et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nature medicine. 2016.", "doi": "10.1038/nm.4040", "pmcid": "PMC4900892", "url": "https://pubmed.ncbi.nlm.nih.gov/26828195/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26828195/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26828195", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "T790M resistance emerges through either pre-existing clones or evolution from tolerant cells; apoptosis-targeted treatment restores sensitivity in a subset.", "what_it_does_not_show": "Patient-derived culture convergence supports distinct paths, not a single universal sequence or permanent dependence on the original inhibitor target.", "confounders_present": [ "Patient-derived culture convergence supports distinct paths, not a single universal sequence or permanent dependence on the original inhibitor target." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "21430269", "title": "Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.", "citation": "Sequist LV, Waltman BA, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science translational medicine. 2011.", "doi": "10.1126/scitranslmed.3002003", "pmcid": "PMC3132801", "url": "https://pubmed.ncbi.nlm.nih.gov/21430269/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21430269/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21430269", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Biopsies from 37 resistant EGFR-mutant lung cancers retain original drivers but show additional genetic or histological changes, including small-cell transition.", "what_it_does_not_show": "Retained driver presence does not prove retained dependency; serial samples are selected resistant cases and not randomized mechanism perturbations.", "confounders_present": [ "Retained driver presence does not prove retained dependency; serial samples are selected resistant cases and not randomized mechanism perturbations." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "31988000", "title": "RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies.", "citation": "Solomon BJ, Tan L, Lin JJ et al. RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2020.", "doi": "10.1016/j.jtho.2020.01.006", "pmcid": "PMC7430178", "url": "https://pubmed.ncbi.nlm.nih.gov/31988000/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31988000/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31988000", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human tissue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition.", "what_it_does_not_show": "Small selected resistance series, shared pathway inhibitors and xenografts do not quantify pan-cancer mutation primacy or exclude state-based escape.", "confounders_present": [ "Small selected resistance series, shared pathway inhibitors and xenografts do not quantify pan-cancer mutation primacy or exclude state-based escape." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "12637609", "title": "Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.", "citation": "O'Brien SG, Guilhot F, Larson RA et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. The New England journal of medicine. 2003.", "doi": "10.1056/NEJMoa022457", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12637609/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12637609/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "IRIS-randomization", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "1106-person IRIS randomization improves cytogenetic response and freedom from blast/accelerated progression with BCR-ABL-directed imatinib.", "what_it_does_not_show": "Drug effects are pathway perturbation rather than correction of the chromosome fusion; crossover and additional kinase targets limit isolated genetic mediation.", "confounders_present": [ "Drug effects are pathway perturbation rather than correction of the chromosome fusion; crossover and additional kinase targets limit isolated genetic mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 60, "pmid": "28273028", "title": "Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia.", "citation": "Hochhaus A, Larson RA, Guilhot F et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. The New England journal of medicine. 2017.", "doi": "10.1056/NEJMoa1609324", "pmcid": "PMC5901965", "url": "https://pubmed.ncbi.nlm.nih.gov/28273028/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28273028/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "IRIS-randomization", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "IRIS long-term follow-up reports sustained imatinib efficacy and 83.3 percent estimated ten-year survival.", "what_it_does_not_show": "Same original randomized cohort; heavy crossover means this survival estimate is not an independent randomized survival comparison or cure of every stem cell.", "confounders_present": [ "Same original randomized cohort; heavy crossover means this survival estimate is not an independent randomized survival comparison or cure of every stem cell." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Same IRIS patients and extensive crossover; not a fresh randomized survival replication." ] }, { "n": 61, "pmid": "39241959", "title": "A randomized study of 6 versus 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse.", "citation": "Blay JY, Schiffler C, Bouché O et al. A randomized study of 6 versus 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse. Annals of oncology : official journal of the European Society for Medical Oncology. 2024.", "doi": "10.1016/j.annonc.2024.08.2343", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39241959/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39241959/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39241959", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "IMADGIST randomizes 136 high-risk resected GIST patients after three years of imatinib; continuation improves disease-free survival.", "what_it_does_not_show": "No survival difference is demonstrated; treatment-selected GIST and KIT/PDGFRA pathway targeting do not generalize to all tumors or establish mutation order.", "confounders_present": [ "No survival difference is demonstrated; treatment-selected GIST and KIT/PDGFRA pathway targeting do not generalize to all tumors or establish mutation order." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 62, "pmid": "29151359", "title": "Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer.", "citation": "Soria JC, Ohe Y, Vansteenkiste J et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. The New England journal of medicine. 2018.", "doi": "10.1056/NEJMoa1713137", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29151359/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29151359/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "FLAURA-randomization", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "556-person FLAURA compares EGFR inhibitors and improves PFS with osimertinib in defined sensitizing mutations.", "what_it_does_not_show": "Both arms inhibit EGFR, so comparative efficacy also reflects drug properties; interim overall survival did not meet its statistical boundary.", "confounders_present": [ "Both arms inhibit EGFR, so comparative efficacy also reflects drug properties; interim overall survival did not meet its statistical boundary." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 63, "pmid": "31751012", "title": "Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC.", "citation": "Ramalingam SS, Vansteenkiste J, Planchard D et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. The New England journal of medicine. 2020.", "doi": "10.1056/NEJMoa1913662", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31751012/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31751012/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "FLAURA-randomization", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Planned FLAURA secondary survival analysis favors osimertinib, median 38.6 versus 31.8 months.", "what_it_does_not_show": "Same FLAURA patients, not a separate replication; more effective genotype-matched drugs support dependency without proving unselected pan-cancer dominance.", "confounders_present": [ "Same FLAURA patients, not a separate replication; more effective genotype-matched drugs support dependency without proving unselected pan-cancer dominance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Same FLAURA patients; secondary survival report." ] }, { "n": 64, "pmid": "37272535", "title": "Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC.", "citation": "Tsuboi M, Herbst RS, John T et al. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. The New England journal of medicine. 2023.", "doi": "10.1056/NEJMoa2304594", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37272535/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37272535/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37272535", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "682-person ADAURA adjuvant randomization improves overall survival after EGFR-mutant lung-cancer resection, with or without prior chemotherapy.", "what_it_does_not_show": "Defined stages and mutations plus surgery constrain scope; therapeutic consequence does not directly establish spontaneous initiation or universal sufficiency.", "confounders_present": [ "Defined stages and mutations plus surgery constrain scope; therapeutic consequence does not directly establish spontaneous initiation or universal sufficiency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 65, "pmid": "28586279", "title": "Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer.", "citation": "Peters S, Camidge DR, Shaw AT et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. The New England journal of medicine. 2017.", "doi": "10.1056/NEJMoa1704795", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28586279/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28586279/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28586279", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "303-person ALEX improves PFS and CNS progression with alectinib versus crizotinib in ALK-positive lung cancer.", "what_it_does_not_show": "Both arms target ALK; pharmacology and CNS penetration differ, and initial report does not establish overall-survival benefit or universal ALK dependence.", "confounders_present": [ "Both arms target ALK; pharmacology and CNS penetration differ, and initial report does not establish overall-survival benefit or universal ALK dependence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 66, "pmid": "37870973", "title": "First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC.", "citation": "Zhou C, Solomon B, Loong HH et al. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. The New England journal of medicine. 2023.", "doi": "10.1056/NEJMoa2309457", "pmcid": "PMC10698285", "url": "https://pubmed.ncbi.nlm.nih.gov/37870973/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37870973/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37870973", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "LIBRETTO-431 compares selective RET inhibition with chemotherapy with/without pembrolizumab and improves PFS in fusion-positive lung cancer.", "what_it_does_not_show": "A structural rearrangement is genetic driver evidence; selected advanced disease and immature/crossover survival do not establish all-cancer primacy.", "confounders_present": [ "A structural rearrangement is genetic driver evidence; selected advanced disease and immature/crossover survival do not establish all-cancer primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 67, "pmid": "21639808", "title": "Improved survival with vemurafenib in melanoma with BRAF V600E mutation.", "citation": "Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England journal of medicine. 2011.", "doi": "10.1056/NEJMoa1103782", "pmcid": "PMC3549296", "url": "https://pubmed.ncbi.nlm.nih.gov/21639808/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21639808/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21639808", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "675-person BRIM3 improves survival and PFS with vemurafenib versus dacarbazine in BRAF V600E melanoma.", "what_it_does_not_show": "Clinical selection and eventual resistance constrain durability; target inhibition does not correct every mutation or remove tissue/immune mediation.", "confounders_present": [ "Clinical selection and eventual resistance constrain durability; target inhibition does not correct every mutation or remove tissue/immune mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 68, "pmid": "25399551", "title": "Improved overall survival in melanoma with combined dabrafenib and trametinib.", "citation": "Robert C, Karaszewska B, Schachter J et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. The New England journal of medicine. 2015.", "doi": "10.1056/NEJMoa1412690", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25399551/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25399551/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25399551", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "704-person COMBI-v improves overall survival with BRAF/MEK combination versus vemurafenib in BRAF V600 melanoma.", "what_it_does_not_show": "A downstream combination strengthens consequence and resistance control, not mutation-only origin; distinct from BRIM3 despite related drug pathway.", "confounders_present": [ "A downstream combination strengthens consequence and resistance control, not mutation-only origin; distinct from BRIM3 despite related drug pathway." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 69, "pmid": "36764316", "title": "Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial.", "citation": "de Langen AJ, Johnson ML, Mazieres J et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. Lancet (London, England). 2023.", "doi": "10.1016/S0140-6736(23)00221-0", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36764316/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36764316/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36764316", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "345-person CodeBreaK200 improves PFS with sotorasib versus docetaxel in previously treated KRAS G12C lung cancer.", "what_it_does_not_show": "The benefit is modest and this abstract does not establish overall-survival benefit; mutation-specific dependence varies by disease and treatment stage.", "confounders_present": [ "The benefit is modest and this abstract does not establish overall-survival benefit; mutation-specific dependence varies by disease and treatment stage." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 70, "pmid": "37870969", "title": "Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer.", "citation": "Hadoux J, Elisei R, Brose MS et al. Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer. The New England journal of medicine. 2023.", "doi": "10.1056/NEJMoa2309719", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37870969/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37870969/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37870969", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "291-person LIBRETTO-531 improves PFS with selective RET inhibition versus multikinase inhibitors in RET-mutant medullary thyroid cancer.", "what_it_does_not_show": "RET alterations may be inherited or somatic; this cohort cannot be counted as a purely somatic initiating-mutation experiment. Both arms target RET-pathway activity.", "confounders_present": [ "RET alterations may be inherited or somatic; this cohort cannot be counted as a purely somatic initiating-mutation experiment. Both arms target RET-pathway activity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 74, "verified": 74, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Sequential somatic driver mutations are the primary initiating and sustaining cause of cancer.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "The cancer rubric explicitly accepts endogenous genetic manipulation, matched restoration and functional clonal dependency. Organoid or transplant initiation alone remains Γ for spontaneous broad inference, but it is not the whole evidence set. Endogenous Kras/p53, reversible endogenous APC protein, native clone competition and genotype-selected clinical consequences cover different failure modes. SC2 earns Η in its genotype-defined scope. SC3 earns Ε from real context-specific causal validity with broader dominance unresolved; it is not capped at Γ because some contributing assays are cultured. Epigenetic mark correlations alone are not credited as causal, while transient endogenous Polycomb depletion with persistent native fly neoplasia is distinguished from transplantation alone.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID37828026, PMID25924068, PMID25706875, PMID39487295, PMID26700815, PMID31988000", "gamma_hard_rules_triggered": [], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Recurrent alterations are distinguished from passengers by selection, clonal timing and precise functional perturbations in specific histologies. Independent genome platforms and autochthonous editing reduce sequencing-error and correlation-only explanations. Genomic annotation alone remains insufficient, and fitness in normal tissue is not necessarily cancer-driving fitness. Ζ is supported across assay classes; most claimed variant classes have not individually received therapeutic/endogenous confirmation, so Η is not assigned to every driver-identification inference.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID34646013, PMID9054499, PMID37828026, PMID34079124, PMID17251932, PMID15894267, PMID14706336, PMID11751630, PMID23226501, PMID14966562, PMID22232209, PMID10488335, PMID15475948, PMID23467612, PMID12098700, PMID21035406, PMID25924068, PMID25706875, PMID28270604, PMID39487295, PMID26091037, PMID38658752, PMID16169468, PMID24856586, PMID16251424, PMID29560858, PMID9105051, PMID37020004, PMID14996910, PMID17189715, PMID20173739, PMID1059147, PMID24529372, PMID26700815, PMID28607484, PMID20371346, PMID37407818, PMID26828195, PMID31988000, PMID12637609, PMID39241959, PMID29151359, PMID31751012, PMID37272535, PMID28586279, PMID37870973, PMID21639808, PMID25399551, PMID36764316, PMID37870969", "gamma_hard_rules_triggered": [], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Endogenous Kras combinations, endogenous p53 restoration, reversible APC loss/restoration and lineage-marked tumor differentiation establish causal dependencies in defined cancers. Multiple genotype-selected clinical trials yield progression or survival consequences across EGFR, BRAF, RET, ALK and BCR-ABL settings. These complementary lines fail differently and satisfy Η in the prespecified genotype-defined scope. The subclaim is initiation OR maintenance, not a requirement that each report establish both. Residual states, relapse and incomplete target response prevent Θ/Ω for most cancer behavior or universal necessity/sufficiency.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID34646013, PMID9054499, PMID37828026, PMID34079124, PMID17251932, PMID15894267, PMID14706336, PMID11751630, PMID23226501, PMID14966562, PMID22232209, PMID10488335, PMID15475948, PMID23467612, PMID12098700, PMID21035406, PMID25924068, PMID25706875, PMID28270604, PMID39487295, PMID26091037, PMID38658752, PMID16169468, PMID24856586, PMID16251424, PMID29560858, PMID9105051, PMID37020004, PMID14996910, PMID17189715, PMID20173739, PMID1059147, PMID24529372, PMID26700815, PMID28607484, PMID20371346, PMID37407818, PMID26828195, PMID31988000, PMID12637609, PMID39241959, PMID29151359, PMID31751012, PMID37272535, PMID28586279, PMID37870973, PMID21639808, PMID25399551, PMID36764316, PMID37870969", "gamma_hard_rules_triggered": [], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Genetic alterations are primary drivers in many tested cancers, with causal initiation and ongoing dependency, rather than mere passengers. Their phenotypic output depends on lineage, niche, immunity and chromatin; tissue mediation may be downstream of the genetic lesion and is not automatically an exclusive rival. Normal mutant tissues show insufficiency, fly/reprogramming models demonstrate bounded alternative initiation, and relapse can change dependence. Ε credits the real causal model while restricting the broad dominant-sequential initiating-and-sustaining claim. This is not a finding that common cancers generally lack driver mutations.", "ceiling_from_boundary_check": "Δ or higher" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "yes", "supporting_evidence": [ "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Η", "requirement_quoted": "Requires:\n- Strong endogenous evidence\n- Therapeutic or mechanistic consequence\n- Reproducibility across disease settings within the claimed scope", "satisfied": "no", "supporting_evidence": [ "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition." ], "what_would_cross_it": "Prospectively validate predicted driver-versus-passenger status across prespecified mutation classes with matched endogenous loss/restoration, patient allele-resolved consequence and reproducibility across histologies." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[15] Endogenous mouse esophageal carcinogenesis and competitive-clone induction/inhibition show mutant neighboring epithelium can eliminate nascent tumors.", "[19] Oncogenic RAS induces arrest in primary cells; p53/p16 inactivation or E1A permits bypass in defined species and cell systems.", "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[21] Apc-mutant cells secrete NOTUM; genetic or pharmacological inhibition reduces wild-type competition loss, mutant fixation and adenomas.", "[22] Restoring endogenous p53 regresses autochthonous lymphomas and sarcomas with different apoptosis/senescence responses and no detected normal-tissue injury.", "[23] Endogenous Kras G12D and Trp53 R172H cooperate to generate invasive, metastatic pancreatic cancer with genomic instability.", "[24] Physiological mutant Kras expression induces the PanIN spectrum, with low-frequency spontaneous invasive/metastatic progression.", "[25] Conditional endogenous oncogenic Kras permits timed autochthonous lung tumor induction and progression analysis.", "[26] Inducible pancreatic Kras withdrawal regresses primary and metastatic tumors; reactivation rapidly restores disease.", "[27] Conditional oncogenic Kras from its endogenous promoter causes fully penetrant myeloproliferation but not transplantable AML.", "[28] Reversible pancreas-specific Kras expression induces and maintains lesions, with withdrawal causing regression and changes in fibroinflammatory stroma.", "[29] Conditional MYC expression produces hematologic malignancies that regress after transgene inactivation, with differentiation and restored hematopoiesis.", "[30] MYC-off liver tumors differentiate and become dormant; reactivation restores malignancy with the same comparative-genomic signature.", "[31] Inducible pancreatic MYC tumors regress after inactivation but residual cells rapidly recur on re-expression.", "[32] Brief MYC inactivation produces sustained osteogenic tumor regression; reactivation induces apoptosis instead of recurrence.", "[33] CD4 and thrombospondin functional contrasts show immune remodelling is required for sustained regression after MYC/BCR-ABL inactivation.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[36] Orthotopic engineered organoids show mutation accumulation supports metastasis; specific niche signals restore growth when one oncogenic alteration is absent.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[39] Endogenous APC protein restoration reverses autochthonous colorectal adenomas/carcinomas, including Kras/p53-altered settings, with lineage-marked normal crypt behavior.", "[40] Transient endogenous Polycomb depletion induces persistent native fly neoplasia after protein recovery; serial allografts grow and metastasize.", "[41] Matrix stiffness, integrin/Rho/ERK manipulations and contractility reduction alter malignant architecture in an integrated signaling circuit.", "[42] Genetic depletion of proliferating alphaSMA fibroblasts accelerates pancreatic cancer and worsens survival; anti-CTLA4 partially rescues the altered state.", "[43] Rat mammary stroma age/parity changes tumor incidence and permits normal ducts containing a tumor-origin RAS marker.", "[44] Brief compression induces normal-like malignant breast structures; nitric-oxide inhibition blocks the architectural response.", "[45] Beta1-integrin inhibitory antibody/Fab reverses malignant breast architecture and reduces nude-mouse tumor formation; stimulatory antibody fails.", "[46] PM2.5 promotes EGFR/KRAS-mutant lung lesions; macrophage/IL1beta experiments connect inflammatory promotion to altered epithelial state.", "[47] Rat recombination contrasts place NMU-associated mammary tumor initiation with exposed stroma, independent of epithelial exposure; Ha-ras status does not track all tumors.", "[48] Transient Mad2 overexpression induces chromosome instability and multiple tumor types; sustained Mad2 is unnecessary for maintenance.", "[49] Mad2-mediated chromosome instability increases Kras-independent relapse after initial regression on oncogene withdrawal.", "[50] Malignant teratocarcinoma cells contribute to functional normal tissues and germline after blastocyst incorporation.", "[51] Interrupted in vivo reprogramming induces dysplastic tumors, and tumor-derived iPSCs can form nonneoplastic kidney cells.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[53] Rare melanoma transcriptional states predict resistance and drug-induced reprogramming stabilizes it.", "[54] Single-clone cancer cultures yield reversible persisters; KDM5A depletion reduces tolerance without detectable parental proliferation loss.", "[55] Therapy induces APOBEC3A in persisters; deletion reduces mutations/structural changes and delays resistance, with concordant patient signatures.", "[56] T790M resistance emerges through either pre-existing clones or evolution from tolerant cells; apoptosis-targeted treatment restores sensitivity in a subset.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition.", "[59] 1106-person IRIS randomization improves cytogenetic response and freedom from blast/accelerated progression with BCR-ABL-directed imatinib.", "[61] IMADGIST randomizes 136 high-risk resected GIST patients after three years of imatinib; continuation improves disease-free survival.", "[62] 556-person FLAURA compares EGFR inhibitors and improves PFS with osimertinib in defined sensitizing mutations.", "[63] Planned FLAURA secondary survival analysis favors osimertinib, median 38.6 versus 31.8 months.", "[64] 682-person ADAURA adjuvant randomization improves overall survival after EGFR-mutant lung-cancer resection, with or without prior chemotherapy.", "[65] 303-person ALEX improves PFS and CNS progression with alectinib versus crizotinib in ALK-positive lung cancer.", "[66] LIBRETTO-431 compares selective RET inhibition with chemotherapy with/without pembrolizumab and improves PFS in fusion-positive lung cancer.", "[67] 675-person BRIM3 improves survival and PFS with vemurafenib versus dacarbazine in BRAF V600E melanoma.", "[68] 704-person COMBI-v improves overall survival with BRAF/MEK combination versus vemurafenib in BRAF V600 melanoma.", "[69] 345-person CodeBreaK200 improves PFS with sotorasib versus docetaxel in previously treated KRAS G12C lung cancer.", "[70] 291-person LIBRETTO-531 improves PFS with selective RET inhibition versus multikinase inhibitors in RET-mutant medullary thyroid cancer." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[15] Endogenous mouse esophageal carcinogenesis and competitive-clone induction/inhibition show mutant neighboring epithelium can eliminate nascent tumors.", "[19] Oncogenic RAS induces arrest in primary cells; p53/p16 inactivation or E1A permits bypass in defined species and cell systems.", "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[21] Apc-mutant cells secrete NOTUM; genetic or pharmacological inhibition reduces wild-type competition loss, mutant fixation and adenomas.", "[22] Restoring endogenous p53 regresses autochthonous lymphomas and sarcomas with different apoptosis/senescence responses and no detected normal-tissue injury.", "[23] Endogenous Kras G12D and Trp53 R172H cooperate to generate invasive, metastatic pancreatic cancer with genomic instability.", "[24] Physiological mutant Kras expression induces the PanIN spectrum, with low-frequency spontaneous invasive/metastatic progression.", "[25] Conditional endogenous oncogenic Kras permits timed autochthonous lung tumor induction and progression analysis.", "[26] Inducible pancreatic Kras withdrawal regresses primary and metastatic tumors; reactivation rapidly restores disease.", "[27] Conditional oncogenic Kras from its endogenous promoter causes fully penetrant myeloproliferation but not transplantable AML.", "[28] Reversible pancreas-specific Kras expression induces and maintains lesions, with withdrawal causing regression and changes in fibroinflammatory stroma.", "[29] Conditional MYC expression produces hematologic malignancies that regress after transgene inactivation, with differentiation and restored hematopoiesis.", "[30] MYC-off liver tumors differentiate and become dormant; reactivation restores malignancy with the same comparative-genomic signature.", "[31] Inducible pancreatic MYC tumors regress after inactivation but residual cells rapidly recur on re-expression.", "[32] Brief MYC inactivation produces sustained osteogenic tumor regression; reactivation induces apoptosis instead of recurrence.", "[33] CD4 and thrombospondin functional contrasts show immune remodelling is required for sustained regression after MYC/BCR-ABL inactivation.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[36] Orthotopic engineered organoids show mutation accumulation supports metastasis; specific niche signals restore growth when one oncogenic alteration is absent.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[39] Endogenous APC protein restoration reverses autochthonous colorectal adenomas/carcinomas, including Kras/p53-altered settings, with lineage-marked normal crypt behavior.", "[40] Transient endogenous Polycomb depletion induces persistent native fly neoplasia after protein recovery; serial allografts grow and metastasize.", "[41] Matrix stiffness, integrin/Rho/ERK manipulations and contractility reduction alter malignant architecture in an integrated signaling circuit.", "[42] Genetic depletion of proliferating alphaSMA fibroblasts accelerates pancreatic cancer and worsens survival; anti-CTLA4 partially rescues the altered state.", "[43] Rat mammary stroma age/parity changes tumor incidence and permits normal ducts containing a tumor-origin RAS marker.", "[44] Brief compression induces normal-like malignant breast structures; nitric-oxide inhibition blocks the architectural response.", "[45] Beta1-integrin inhibitory antibody/Fab reverses malignant breast architecture and reduces nude-mouse tumor formation; stimulatory antibody fails.", "[46] PM2.5 promotes EGFR/KRAS-mutant lung lesions; macrophage/IL1beta experiments connect inflammatory promotion to altered epithelial state.", "[47] Rat recombination contrasts place NMU-associated mammary tumor initiation with exposed stroma, independent of epithelial exposure; Ha-ras status does not track all tumors.", "[48] Transient Mad2 overexpression induces chromosome instability and multiple tumor types; sustained Mad2 is unnecessary for maintenance.", "[49] Mad2-mediated chromosome instability increases Kras-independent relapse after initial regression on oncogene withdrawal.", "[50] Malignant teratocarcinoma cells contribute to functional normal tissues and germline after blastocyst incorporation.", "[51] Interrupted in vivo reprogramming induces dysplastic tumors, and tumor-derived iPSCs can form nonneoplastic kidney cells.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[53] Rare melanoma transcriptional states predict resistance and drug-induced reprogramming stabilizes it.", "[54] Single-clone cancer cultures yield reversible persisters; KDM5A depletion reduces tolerance without detectable parental proliferation loss.", "[55] Therapy induces APOBEC3A in persisters; deletion reduces mutations/structural changes and delays resistance, with concordant patient signatures.", "[56] T790M resistance emerges through either pre-existing clones or evolution from tolerant cells; apoptosis-targeted treatment restores sensitivity in a subset.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition.", "[59] 1106-person IRIS randomization improves cytogenetic response and freedom from blast/accelerated progression with BCR-ABL-directed imatinib.", "[61] IMADGIST randomizes 136 high-risk resected GIST patients after three years of imatinib; continuation improves disease-free survival.", "[62] 556-person FLAURA compares EGFR inhibitors and improves PFS with osimertinib in defined sensitizing mutations.", "[63] Planned FLAURA secondary survival analysis favors osimertinib, median 38.6 versus 31.8 months.", "[64] 682-person ADAURA adjuvant randomization improves overall survival after EGFR-mutant lung-cancer resection, with or without prior chemotherapy.", "[65] 303-person ALEX improves PFS and CNS progression with alectinib versus crizotinib in ALK-positive lung cancer.", "[66] LIBRETTO-431 compares selective RET inhibition with chemotherapy with/without pembrolizumab and improves PFS in fusion-positive lung cancer.", "[67] 675-person BRIM3 improves survival and PFS with vemurafenib versus dacarbazine in BRAF V600E melanoma.", "[68] 704-person COMBI-v improves overall survival with BRAF/MEK combination versus vemurafenib in BRAF V600 melanoma.", "[69] 345-person CodeBreaK200 improves PFS with sotorasib versus docetaxel in previously treated KRAS G12C lung cancer.", "[70] 291-person LIBRETTO-531 improves PFS with selective RET inhibition versus multikinase inhibitors in RET-mutant medullary thyroid cancer." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "yes", "supporting_evidence": [ "[15] Endogenous mouse esophageal carcinogenesis and competitive-clone induction/inhibition show mutant neighboring epithelium can eliminate nascent tumors.", "[19] Oncogenic RAS induces arrest in primary cells; p53/p16 inactivation or E1A permits bypass in defined species and cell systems.", "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[21] Apc-mutant cells secrete NOTUM; genetic or pharmacological inhibition reduces wild-type competition loss, mutant fixation and adenomas.", "[22] Restoring endogenous p53 regresses autochthonous lymphomas and sarcomas with different apoptosis/senescence responses and no detected normal-tissue injury.", "[23] Endogenous Kras G12D and Trp53 R172H cooperate to generate invasive, metastatic pancreatic cancer with genomic instability.", "[24] Physiological mutant Kras expression induces the PanIN spectrum, with low-frequency spontaneous invasive/metastatic progression.", "[25] Conditional endogenous oncogenic Kras permits timed autochthonous lung tumor induction and progression analysis.", "[26] Inducible pancreatic Kras withdrawal regresses primary and metastatic tumors; reactivation rapidly restores disease.", "[27] Conditional oncogenic Kras from its endogenous promoter causes fully penetrant myeloproliferation but not transplantable AML.", "[28] Reversible pancreas-specific Kras expression induces and maintains lesions, with withdrawal causing regression and changes in fibroinflammatory stroma.", "[29] Conditional MYC expression produces hematologic malignancies that regress after transgene inactivation, with differentiation and restored hematopoiesis.", "[30] MYC-off liver tumors differentiate and become dormant; reactivation restores malignancy with the same comparative-genomic signature.", "[31] Inducible pancreatic MYC tumors regress after inactivation but residual cells rapidly recur on re-expression.", "[32] Brief MYC inactivation produces sustained osteogenic tumor regression; reactivation induces apoptosis instead of recurrence.", "[33] CD4 and thrombospondin functional contrasts show immune remodelling is required for sustained regression after MYC/BCR-ABL inactivation.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[36] Orthotopic engineered organoids show mutation accumulation supports metastasis; specific niche signals restore growth when one oncogenic alteration is absent.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[39] Endogenous APC protein restoration reverses autochthonous colorectal adenomas/carcinomas, including Kras/p53-altered settings, with lineage-marked normal crypt behavior.", "[40] Transient endogenous Polycomb depletion induces persistent native fly neoplasia after protein recovery; serial allografts grow and metastasize.", "[41] Matrix stiffness, integrin/Rho/ERK manipulations and contractility reduction alter malignant architecture in an integrated signaling circuit.", "[42] Genetic depletion of proliferating alphaSMA fibroblasts accelerates pancreatic cancer and worsens survival; anti-CTLA4 partially rescues the altered state.", "[43] Rat mammary stroma age/parity changes tumor incidence and permits normal ducts containing a tumor-origin RAS marker.", "[44] Brief compression induces normal-like malignant breast structures; nitric-oxide inhibition blocks the architectural response.", "[45] Beta1-integrin inhibitory antibody/Fab reverses malignant breast architecture and reduces nude-mouse tumor formation; stimulatory antibody fails.", "[46] PM2.5 promotes EGFR/KRAS-mutant lung lesions; macrophage/IL1beta experiments connect inflammatory promotion to altered epithelial state.", "[47] Rat recombination contrasts place NMU-associated mammary tumor initiation with exposed stroma, independent of epithelial exposure; Ha-ras status does not track all tumors.", "[48] Transient Mad2 overexpression induces chromosome instability and multiple tumor types; sustained Mad2 is unnecessary for maintenance.", "[49] Mad2-mediated chromosome instability increases Kras-independent relapse after initial regression on oncogene withdrawal.", "[50] Malignant teratocarcinoma cells contribute to functional normal tissues and germline after blastocyst incorporation.", "[51] Interrupted in vivo reprogramming induces dysplastic tumors, and tumor-derived iPSCs can form nonneoplastic kidney cells.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[53] Rare melanoma transcriptional states predict resistance and drug-induced reprogramming stabilizes it.", "[54] Single-clone cancer cultures yield reversible persisters; KDM5A depletion reduces tolerance without detectable parental proliferation loss.", "[55] Therapy induces APOBEC3A in persisters; deletion reduces mutations/structural changes and delays resistance, with concordant patient signatures.", "[56] T790M resistance emerges through either pre-existing clones or evolution from tolerant cells; apoptosis-targeted treatment restores sensitivity in a subset.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition.", "[59] 1106-person IRIS randomization improves cytogenetic response and freedom from blast/accelerated progression with BCR-ABL-directed imatinib.", "[61] IMADGIST randomizes 136 high-risk resected GIST patients after three years of imatinib; continuation improves disease-free survival.", "[62] 556-person FLAURA compares EGFR inhibitors and improves PFS with osimertinib in defined sensitizing mutations.", "[63] Planned FLAURA secondary survival analysis favors osimertinib, median 38.6 versus 31.8 months.", "[64] 682-person ADAURA adjuvant randomization improves overall survival after EGFR-mutant lung-cancer resection, with or without prior chemotherapy.", "[65] 303-person ALEX improves PFS and CNS progression with alectinib versus crizotinib in ALK-positive lung cancer.", "[66] LIBRETTO-431 compares selective RET inhibition with chemotherapy with/without pembrolizumab and improves PFS in fusion-positive lung cancer.", "[67] 675-person BRIM3 improves survival and PFS with vemurafenib versus dacarbazine in BRAF V600E melanoma.", "[68] 704-person COMBI-v improves overall survival with BRAF/MEK combination versus vemurafenib in BRAF V600 melanoma.", "[69] 345-person CodeBreaK200 improves PFS with sotorasib versus docetaxel in previously treated KRAS G12C lung cancer.", "[70] 291-person LIBRETTO-531 improves PFS with selective RET inhibition versus multikinase inhibitors in RET-mutant medullary thyroid cancer." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Η", "requirement_quoted": "Requires:\n- Strong endogenous evidence\n- Therapeutic or mechanistic consequence\n- Reproducibility across disease settings within the claimed scope", "satisfied": "yes", "supporting_evidence": [ "[15] Endogenous mouse esophageal carcinogenesis and competitive-clone induction/inhibition show mutant neighboring epithelium can eliminate nascent tumors.", "[19] Oncogenic RAS induces arrest in primary cells; p53/p16 inactivation or E1A permits bypass in defined species and cell systems.", "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[21] Apc-mutant cells secrete NOTUM; genetic or pharmacological inhibition reduces wild-type competition loss, mutant fixation and adenomas.", "[22] Restoring endogenous p53 regresses autochthonous lymphomas and sarcomas with different apoptosis/senescence responses and no detected normal-tissue injury.", "[23] Endogenous Kras G12D and Trp53 R172H cooperate to generate invasive, metastatic pancreatic cancer with genomic instability.", "[24] Physiological mutant Kras expression induces the PanIN spectrum, with low-frequency spontaneous invasive/metastatic progression.", "[25] Conditional endogenous oncogenic Kras permits timed autochthonous lung tumor induction and progression analysis.", "[26] Inducible pancreatic Kras withdrawal regresses primary and metastatic tumors; reactivation rapidly restores disease.", "[27] Conditional oncogenic Kras from its endogenous promoter causes fully penetrant myeloproliferation but not transplantable AML.", "[28] Reversible pancreas-specific Kras expression induces and maintains lesions, with withdrawal causing regression and changes in fibroinflammatory stroma.", "[29] Conditional MYC expression produces hematologic malignancies that regress after transgene inactivation, with differentiation and restored hematopoiesis.", "[30] MYC-off liver tumors differentiate and become dormant; reactivation restores malignancy with the same comparative-genomic signature.", "[31] Inducible pancreatic MYC tumors regress after inactivation but residual cells rapidly recur on re-expression.", "[32] Brief MYC inactivation produces sustained osteogenic tumor regression; reactivation induces apoptosis instead of recurrence.", "[33] CD4 and thrombospondin functional contrasts show immune remodelling is required for sustained regression after MYC/BCR-ABL inactivation.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[36] Orthotopic engineered organoids show mutation accumulation supports metastasis; specific niche signals restore growth when one oncogenic alteration is absent.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[39] Endogenous APC protein restoration reverses autochthonous colorectal adenomas/carcinomas, including Kras/p53-altered settings, with lineage-marked normal crypt behavior.", "[40] Transient endogenous Polycomb depletion induces persistent native fly neoplasia after protein recovery; serial allografts grow and metastasize.", "[41] Matrix stiffness, integrin/Rho/ERK manipulations and contractility reduction alter malignant architecture in an integrated signaling circuit.", "[42] Genetic depletion of proliferating alphaSMA fibroblasts accelerates pancreatic cancer and worsens survival; anti-CTLA4 partially rescues the altered state.", "[43] Rat mammary stroma age/parity changes tumor incidence and permits normal ducts containing a tumor-origin RAS marker.", "[44] Brief compression induces normal-like malignant breast structures; nitric-oxide inhibition blocks the architectural response.", "[45] Beta1-integrin inhibitory antibody/Fab reverses malignant breast architecture and reduces nude-mouse tumor formation; stimulatory antibody fails.", "[46] PM2.5 promotes EGFR/KRAS-mutant lung lesions; macrophage/IL1beta experiments connect inflammatory promotion to altered epithelial state.", "[47] Rat recombination contrasts place NMU-associated mammary tumor initiation with exposed stroma, independent of epithelial exposure; Ha-ras status does not track all tumors.", "[48] Transient Mad2 overexpression induces chromosome instability and multiple tumor types; sustained Mad2 is unnecessary for maintenance.", "[49] Mad2-mediated chromosome instability increases Kras-independent relapse after initial regression on oncogene withdrawal.", "[50] Malignant teratocarcinoma cells contribute to functional normal tissues and germline after blastocyst incorporation.", "[51] Interrupted in vivo reprogramming induces dysplastic tumors, and tumor-derived iPSCs can form nonneoplastic kidney cells.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[53] Rare melanoma transcriptional states predict resistance and drug-induced reprogramming stabilizes it.", "[54] Single-clone cancer cultures yield reversible persisters; KDM5A depletion reduces tolerance without detectable parental proliferation loss.", "[55] Therapy induces APOBEC3A in persisters; deletion reduces mutations/structural changes and delays resistance, with concordant patient signatures.", "[56] T790M resistance emerges through either pre-existing clones or evolution from tolerant cells; apoptosis-targeted treatment restores sensitivity in a subset.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition.", "[59] 1106-person IRIS randomization improves cytogenetic response and freedom from blast/accelerated progression with BCR-ABL-directed imatinib.", "[61] IMADGIST randomizes 136 high-risk resected GIST patients after three years of imatinib; continuation improves disease-free survival.", "[62] 556-person FLAURA compares EGFR inhibitors and improves PFS with osimertinib in defined sensitizing mutations.", "[63] Planned FLAURA secondary survival analysis favors osimertinib, median 38.6 versus 31.8 months.", "[64] 682-person ADAURA adjuvant randomization improves overall survival after EGFR-mutant lung-cancer resection, with or without prior chemotherapy.", "[65] 303-person ALEX improves PFS and CNS progression with alectinib versus crizotinib in ALK-positive lung cancer.", "[66] LIBRETTO-431 compares selective RET inhibition with chemotherapy with/without pembrolizumab and improves PFS in fusion-positive lung cancer.", "[67] 675-person BRIM3 improves survival and PFS with vemurafenib versus dacarbazine in BRAF V600E melanoma.", "[68] 704-person COMBI-v improves overall survival with BRAF/MEK combination versus vemurafenib in BRAF V600 melanoma.", "[69] 345-person CodeBreaK200 improves PFS with sotorasib versus docetaxel in previously treated KRAS G12C lung cancer.", "[70] 291-person LIBRETTO-531 improves PFS with selective RET inhibition versus multikinase inhibitors in RET-mutant medullary thyroid cancer." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Θ", "requirement_quoted": "Requires that the mechanism explains most of the claimed cancer behavior with only minor exceptions.", "satisfied": "no", "supporting_evidence": [ "[15] Endogenous mouse esophageal carcinogenesis and competitive-clone induction/inhibition show mutant neighboring epithelium can eliminate nascent tumors.", "[19] Oncogenic RAS induces arrest in primary cells; p53/p16 inactivation or E1A permits bypass in defined species and cell systems.", "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[21] Apc-mutant cells secrete NOTUM; genetic or pharmacological inhibition reduces wild-type competition loss, mutant fixation and adenomas.", "[22] Restoring endogenous p53 regresses autochthonous lymphomas and sarcomas with different apoptosis/senescence responses and no detected normal-tissue injury.", "[23] Endogenous Kras G12D and Trp53 R172H cooperate to generate invasive, metastatic pancreatic cancer with genomic instability.", "[24] Physiological mutant Kras expression induces the PanIN spectrum, with low-frequency spontaneous invasive/metastatic progression.", "[25] Conditional endogenous oncogenic Kras permits timed autochthonous lung tumor induction and progression analysis.", "[26] Inducible pancreatic Kras withdrawal regresses primary and metastatic tumors; reactivation rapidly restores disease.", "[27] Conditional oncogenic Kras from its endogenous promoter causes fully penetrant myeloproliferation but not transplantable AML.", "[28] Reversible pancreas-specific Kras expression induces and maintains lesions, with withdrawal causing regression and changes in fibroinflammatory stroma.", "[29] Conditional MYC expression produces hematologic malignancies that regress after transgene inactivation, with differentiation and restored hematopoiesis.", "[30] MYC-off liver tumors differentiate and become dormant; reactivation restores malignancy with the same comparative-genomic signature.", "[31] Inducible pancreatic MYC tumors regress after inactivation but residual cells rapidly recur on re-expression.", "[32] Brief MYC inactivation produces sustained osteogenic tumor regression; reactivation induces apoptosis instead of recurrence.", "[33] CD4 and thrombospondin functional contrasts show immune remodelling is required for sustained regression after MYC/BCR-ABL inactivation.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[36] Orthotopic engineered organoids show mutation accumulation supports metastasis; specific niche signals restore growth when one oncogenic alteration is absent.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[39] Endogenous APC protein restoration reverses autochthonous colorectal adenomas/carcinomas, including Kras/p53-altered settings, with lineage-marked normal crypt behavior.", "[40] Transient endogenous Polycomb depletion induces persistent native fly neoplasia after protein recovery; serial allografts grow and metastasize.", "[41] Matrix stiffness, integrin/Rho/ERK manipulations and contractility reduction alter malignant architecture in an integrated signaling circuit.", "[42] Genetic depletion of proliferating alphaSMA fibroblasts accelerates pancreatic cancer and worsens survival; anti-CTLA4 partially rescues the altered state.", "[43] Rat mammary stroma age/parity changes tumor incidence and permits normal ducts containing a tumor-origin RAS marker.", "[44] Brief compression induces normal-like malignant breast structures; nitric-oxide inhibition blocks the architectural response.", "[45] Beta1-integrin inhibitory antibody/Fab reverses malignant breast architecture and reduces nude-mouse tumor formation; stimulatory antibody fails.", "[46] PM2.5 promotes EGFR/KRAS-mutant lung lesions; macrophage/IL1beta experiments connect inflammatory promotion to altered epithelial state.", "[47] Rat recombination contrasts place NMU-associated mammary tumor initiation with exposed stroma, independent of epithelial exposure; Ha-ras status does not track all tumors.", "[48] Transient Mad2 overexpression induces chromosome instability and multiple tumor types; sustained Mad2 is unnecessary for maintenance.", "[49] Mad2-mediated chromosome instability increases Kras-independent relapse after initial regression on oncogene withdrawal.", "[50] Malignant teratocarcinoma cells contribute to functional normal tissues and germline after blastocyst incorporation.", "[51] Interrupted in vivo reprogramming induces dysplastic tumors, and tumor-derived iPSCs can form nonneoplastic kidney cells.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[53] Rare melanoma transcriptional states predict resistance and drug-induced reprogramming stabilizes it.", "[54] Single-clone cancer cultures yield reversible persisters; KDM5A depletion reduces tolerance without detectable parental proliferation loss.", "[55] Therapy induces APOBEC3A in persisters; deletion reduces mutations/structural changes and delays resistance, with concordant patient signatures.", "[56] T790M resistance emerges through either pre-existing clones or evolution from tolerant cells; apoptosis-targeted treatment restores sensitivity in a subset.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition.", "[59] 1106-person IRIS randomization improves cytogenetic response and freedom from blast/accelerated progression with BCR-ABL-directed imatinib.", "[61] IMADGIST randomizes 136 high-risk resected GIST patients after three years of imatinib; continuation improves disease-free survival.", "[62] 556-person FLAURA compares EGFR inhibitors and improves PFS with osimertinib in defined sensitizing mutations.", "[63] Planned FLAURA secondary survival analysis favors osimertinib, median 38.6 versus 31.8 months.", "[64] 682-person ADAURA adjuvant randomization improves overall survival after EGFR-mutant lung-cancer resection, with or without prior chemotherapy.", "[65] 303-person ALEX improves PFS and CNS progression with alectinib versus crizotinib in ALK-positive lung cancer.", "[66] LIBRETTO-431 compares selective RET inhibition with chemotherapy with/without pembrolizumab and improves PFS in fusion-positive lung cancer.", "[67] 675-person BRIM3 improves survival and PFS with vemurafenib versus dacarbazine in BRAF V600E melanoma.", "[68] 704-person COMBI-v improves overall survival with BRAF/MEK combination versus vemurafenib in BRAF V600 melanoma.", "[69] 345-person CodeBreaK200 improves PFS with sotorasib versus docetaxel in previously treated KRAS G12C lung cancer.", "[70] 291-person LIBRETTO-531 improves PFS with selective RET inhibition versus multikinase inhibitors in RET-mutant medullary thyroid cancer." ], "what_would_cross_it": "Demonstrate that these dependencies explain most initiation, maintenance and relapse behavior in the registered genotype-defined settings, with only minor exceptions and durable rescue after verified selective engagement." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[15] Endogenous mouse esophageal carcinogenesis and competitive-clone induction/inhibition show mutant neighboring epithelium can eliminate nascent tumors.", "[19] Oncogenic RAS induces arrest in primary cells; p53/p16 inactivation or E1A permits bypass in defined species and cell systems.", "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[21] Apc-mutant cells secrete NOTUM; genetic or pharmacological inhibition reduces wild-type competition loss, mutant fixation and adenomas.", "[22] Restoring endogenous p53 regresses autochthonous lymphomas and sarcomas with different apoptosis/senescence responses and no detected normal-tissue injury.", "[23] Endogenous Kras G12D and Trp53 R172H cooperate to generate invasive, metastatic pancreatic cancer with genomic instability.", "[24] Physiological mutant Kras expression induces the PanIN spectrum, with low-frequency spontaneous invasive/metastatic progression.", "[25] Conditional endogenous oncogenic Kras permits timed autochthonous lung tumor induction and progression analysis.", "[26] Inducible pancreatic Kras withdrawal regresses primary and metastatic tumors; reactivation rapidly restores disease.", "[27] Conditional oncogenic Kras from its endogenous promoter causes fully penetrant myeloproliferation but not transplantable AML.", "[28] Reversible pancreas-specific Kras expression induces and maintains lesions, with withdrawal causing regression and changes in fibroinflammatory stroma.", "[29] Conditional MYC expression produces hematologic malignancies that regress after transgene inactivation, with differentiation and restored hematopoiesis.", "[30] MYC-off liver tumors differentiate and become dormant; reactivation restores malignancy with the same comparative-genomic signature.", "[31] Inducible pancreatic MYC tumors regress after inactivation but residual cells rapidly recur on re-expression.", "[32] Brief MYC inactivation produces sustained osteogenic tumor regression; reactivation induces apoptosis instead of recurrence.", "[33] CD4 and thrombospondin functional contrasts show immune remodelling is required for sustained regression after MYC/BCR-ABL inactivation.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[36] Orthotopic engineered organoids show mutation accumulation supports metastasis; specific niche signals restore growth when one oncogenic alteration is absent.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[39] Endogenous APC protein restoration reverses autochthonous colorectal adenomas/carcinomas, including Kras/p53-altered settings, with lineage-marked normal crypt behavior.", "[40] Transient endogenous Polycomb depletion induces persistent native fly neoplasia after protein recovery; serial allografts grow and metastasize.", "[41] Matrix stiffness, integrin/Rho/ERK manipulations and contractility reduction alter malignant architecture in an integrated signaling circuit.", "[42] Genetic depletion of proliferating alphaSMA fibroblasts accelerates pancreatic cancer and worsens survival; anti-CTLA4 partially rescues the altered state.", "[43] Rat mammary stroma age/parity changes tumor incidence and permits normal ducts containing a tumor-origin RAS marker.", "[44] Brief compression induces normal-like malignant breast structures; nitric-oxide inhibition blocks the architectural response.", "[45] Beta1-integrin inhibitory antibody/Fab reverses malignant breast architecture and reduces nude-mouse tumor formation; stimulatory antibody fails.", "[46] PM2.5 promotes EGFR/KRAS-mutant lung lesions; macrophage/IL1beta experiments connect inflammatory promotion to altered epithelial state.", "[47] Rat recombination contrasts place NMU-associated mammary tumor initiation with exposed stroma, independent of epithelial exposure; Ha-ras status does not track all tumors.", "[48] Transient Mad2 overexpression induces chromosome instability and multiple tumor types; sustained Mad2 is unnecessary for maintenance.", "[49] Mad2-mediated chromosome instability increases Kras-independent relapse after initial regression on oncogene withdrawal.", "[50] Malignant teratocarcinoma cells contribute to functional normal tissues and germline after blastocyst incorporation.", "[51] Interrupted in vivo reprogramming induces dysplastic tumors, and tumor-derived iPSCs can form nonneoplastic kidney cells.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[53] Rare melanoma transcriptional states predict resistance and drug-induced reprogramming stabilizes it.", "[54] Single-clone cancer cultures yield reversible persisters; KDM5A depletion reduces tolerance without detectable parental proliferation loss.", "[55] Therapy induces APOBEC3A in persisters; deletion reduces mutations/structural changes and delays resistance, with concordant patient signatures.", "[56] T790M resistance emerges through either pre-existing clones or evolution from tolerant cells; apoptosis-targeted treatment restores sensitivity in a subset.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition.", "[59] 1106-person IRIS randomization improves cytogenetic response and freedom from blast/accelerated progression with BCR-ABL-directed imatinib.", "[61] IMADGIST randomizes 136 high-risk resected GIST patients after three years of imatinib; continuation improves disease-free survival.", "[62] 556-person FLAURA compares EGFR inhibitors and improves PFS with osimertinib in defined sensitizing mutations.", "[63] Planned FLAURA secondary survival analysis favors osimertinib, median 38.6 versus 31.8 months.", "[64] 682-person ADAURA adjuvant randomization improves overall survival after EGFR-mutant lung-cancer resection, with or without prior chemotherapy.", "[65] 303-person ALEX improves PFS and CNS progression with alectinib versus crizotinib in ALK-positive lung cancer.", "[66] LIBRETTO-431 compares selective RET inhibition with chemotherapy with/without pembrolizumab and improves PFS in fusion-positive lung cancer.", "[67] 675-person BRIM3 improves survival and PFS with vemurafenib versus dacarbazine in BRAF V600E melanoma.", "[68] 704-person COMBI-v improves overall survival with BRAF/MEK combination versus vemurafenib in BRAF V600 melanoma.", "[69] 345-person CodeBreaK200 improves PFS with sotorasib versus docetaxel in previously treated KRAS G12C lung cancer.", "[70] 291-person LIBRETTO-531 improves PFS with selective RET inhibition versus multikinase inhibitors in RET-mutant medullary thyroid cancer." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[15] Endogenous mouse esophageal carcinogenesis and competitive-clone induction/inhibition show mutant neighboring epithelium can eliminate nascent tumors.", "[19] Oncogenic RAS induces arrest in primary cells; p53/p16 inactivation or E1A permits bypass in defined species and cell systems.", "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[21] Apc-mutant cells secrete NOTUM; genetic or pharmacological inhibition reduces wild-type competition loss, mutant fixation and adenomas.", "[22] Restoring endogenous p53 regresses autochthonous lymphomas and sarcomas with different apoptosis/senescence responses and no detected normal-tissue injury.", "[23] Endogenous Kras G12D and Trp53 R172H cooperate to generate invasive, metastatic pancreatic cancer with genomic instability.", "[24] Physiological mutant Kras expression induces the PanIN spectrum, with low-frequency spontaneous invasive/metastatic progression.", "[25] Conditional endogenous oncogenic Kras permits timed autochthonous lung tumor induction and progression analysis.", "[26] Inducible pancreatic Kras withdrawal regresses primary and metastatic tumors; reactivation rapidly restores disease.", "[27] Conditional oncogenic Kras from its endogenous promoter causes fully penetrant myeloproliferation but not transplantable AML.", "[28] Reversible pancreas-specific Kras expression induces and maintains lesions, with withdrawal causing regression and changes in fibroinflammatory stroma.", "[29] Conditional MYC expression produces hematologic malignancies that regress after transgene inactivation, with differentiation and restored hematopoiesis.", "[30] MYC-off liver tumors differentiate and become dormant; reactivation restores malignancy with the same comparative-genomic signature.", "[31] Inducible pancreatic MYC tumors regress after inactivation but residual cells rapidly recur on re-expression.", "[32] Brief MYC inactivation produces sustained osteogenic tumor regression; reactivation induces apoptosis instead of recurrence.", "[33] CD4 and thrombospondin functional contrasts show immune remodelling is required for sustained regression after MYC/BCR-ABL inactivation.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[36] Orthotopic engineered organoids show mutation accumulation supports metastasis; specific niche signals restore growth when one oncogenic alteration is absent.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[39] Endogenous APC protein restoration reverses autochthonous colorectal adenomas/carcinomas, including Kras/p53-altered settings, with lineage-marked normal crypt behavior.", "[40] Transient endogenous Polycomb depletion induces persistent native fly neoplasia after protein recovery; serial allografts grow and metastasize.", "[41] Matrix stiffness, integrin/Rho/ERK manipulations and contractility reduction alter malignant architecture in an integrated signaling circuit.", "[42] Genetic depletion of proliferating alphaSMA fibroblasts accelerates pancreatic cancer and worsens survival; anti-CTLA4 partially rescues the altered state.", "[43] Rat mammary stroma age/parity changes tumor incidence and permits normal ducts containing a tumor-origin RAS marker.", "[44] Brief compression induces normal-like malignant breast structures; nitric-oxide inhibition blocks the architectural response.", "[45] Beta1-integrin inhibitory antibody/Fab reverses malignant breast architecture and reduces nude-mouse tumor formation; stimulatory antibody fails.", "[46] PM2.5 promotes EGFR/KRAS-mutant lung lesions; macrophage/IL1beta experiments connect inflammatory promotion to altered epithelial state.", "[47] Rat recombination contrasts place NMU-associated mammary tumor initiation with exposed stroma, independent of epithelial exposure; Ha-ras status does not track all tumors.", "[48] Transient Mad2 overexpression induces chromosome instability and multiple tumor types; sustained Mad2 is unnecessary for maintenance.", "[49] Mad2-mediated chromosome instability increases Kras-independent relapse after initial regression on oncogene withdrawal.", "[50] Malignant teratocarcinoma cells contribute to functional normal tissues and germline after blastocyst incorporation.", "[51] Interrupted in vivo reprogramming induces dysplastic tumors, and tumor-derived iPSCs can form nonneoplastic kidney cells.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[53] Rare melanoma transcriptional states predict resistance and drug-induced reprogramming stabilizes it.", "[54] Single-clone cancer cultures yield reversible persisters; KDM5A depletion reduces tolerance without detectable parental proliferation loss.", "[55] Therapy induces APOBEC3A in persisters; deletion reduces mutations/structural changes and delays resistance, with concordant patient signatures.", "[56] T790M resistance emerges through either pre-existing clones or evolution from tolerant cells; apoptosis-targeted treatment restores sensitivity in a subset.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition.", "[59] 1106-person IRIS randomization improves cytogenetic response and freedom from blast/accelerated progression with BCR-ABL-directed imatinib.", "[61] IMADGIST randomizes 136 high-risk resected GIST patients after three years of imatinib; continuation improves disease-free survival.", "[62] 556-person FLAURA compares EGFR inhibitors and improves PFS with osimertinib in defined sensitizing mutations.", "[63] Planned FLAURA secondary survival analysis favors osimertinib, median 38.6 versus 31.8 months.", "[64] 682-person ADAURA adjuvant randomization improves overall survival after EGFR-mutant lung-cancer resection, with or without prior chemotherapy.", "[65] 303-person ALEX improves PFS and CNS progression with alectinib versus crizotinib in ALK-positive lung cancer.", "[66] LIBRETTO-431 compares selective RET inhibition with chemotherapy with/without pembrolizumab and improves PFS in fusion-positive lung cancer.", "[67] 675-person BRIM3 improves survival and PFS with vemurafenib versus dacarbazine in BRAF V600E melanoma.", "[68] 704-person COMBI-v improves overall survival with BRAF/MEK combination versus vemurafenib in BRAF V600 melanoma.", "[69] 345-person CodeBreaK200 improves PFS with sotorasib versus docetaxel in previously treated KRAS G12C lung cancer.", "[70] 291-person LIBRETTO-531 improves PFS with selective RET inhibition versus multikinase inhibitors in RET-mutant medullary thyroid cancer." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "no", "supporting_evidence": [ "[15] Endogenous mouse esophageal carcinogenesis and competitive-clone induction/inhibition show mutant neighboring epithelium can eliminate nascent tumors.", "[19] Oncogenic RAS induces arrest in primary cells; p53/p16 inactivation or E1A permits bypass in defined species and cell systems.", "[20] Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign.", "[21] Apc-mutant cells secrete NOTUM; genetic or pharmacological inhibition reduces wild-type competition loss, mutant fixation and adenomas.", "[22] Restoring endogenous p53 regresses autochthonous lymphomas and sarcomas with different apoptosis/senescence responses and no detected normal-tissue injury.", "[23] Endogenous Kras G12D and Trp53 R172H cooperate to generate invasive, metastatic pancreatic cancer with genomic instability.", "[24] Physiological mutant Kras expression induces the PanIN spectrum, with low-frequency spontaneous invasive/metastatic progression.", "[25] Conditional endogenous oncogenic Kras permits timed autochthonous lung tumor induction and progression analysis.", "[26] Inducible pancreatic Kras withdrawal regresses primary and metastatic tumors; reactivation rapidly restores disease.", "[27] Conditional oncogenic Kras from its endogenous promoter causes fully penetrant myeloproliferation but not transplantable AML.", "[28] Reversible pancreas-specific Kras expression induces and maintains lesions, with withdrawal causing regression and changes in fibroinflammatory stroma.", "[29] Conditional MYC expression produces hematologic malignancies that regress after transgene inactivation, with differentiation and restored hematopoiesis.", "[30] MYC-off liver tumors differentiate and become dormant; reactivation restores malignancy with the same comparative-genomic signature.", "[31] Inducible pancreatic MYC tumors regress after inactivation but residual cells rapidly recur on re-expression.", "[32] Brief MYC inactivation produces sustained osteogenic tumor regression; reactivation induces apoptosis instead of recurrence.", "[33] CD4 and thrombospondin functional contrasts show immune remodelling is required for sustained regression after MYC/BCR-ABL inactivation.", "[34] Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors.", "[35] Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids.", "[36] Orthotopic engineered organoids show mutation accumulation supports metastasis; specific niche signals restore growth when one oncogenic alteration is absent.", "[37] MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors.", "[39] Endogenous APC protein restoration reverses autochthonous colorectal adenomas/carcinomas, including Kras/p53-altered settings, with lineage-marked normal crypt behavior.", "[40] Transient endogenous Polycomb depletion induces persistent native fly neoplasia after protein recovery; serial allografts grow and metastasize.", "[41] Matrix stiffness, integrin/Rho/ERK manipulations and contractility reduction alter malignant architecture in an integrated signaling circuit.", "[42] Genetic depletion of proliferating alphaSMA fibroblasts accelerates pancreatic cancer and worsens survival; anti-CTLA4 partially rescues the altered state.", "[43] Rat mammary stroma age/parity changes tumor incidence and permits normal ducts containing a tumor-origin RAS marker.", "[44] Brief compression induces normal-like malignant breast structures; nitric-oxide inhibition blocks the architectural response.", "[45] Beta1-integrin inhibitory antibody/Fab reverses malignant breast architecture and reduces nude-mouse tumor formation; stimulatory antibody fails.", "[46] PM2.5 promotes EGFR/KRAS-mutant lung lesions; macrophage/IL1beta experiments connect inflammatory promotion to altered epithelial state.", "[47] Rat recombination contrasts place NMU-associated mammary tumor initiation with exposed stroma, independent of epithelial exposure; Ha-ras status does not track all tumors.", "[48] Transient Mad2 overexpression induces chromosome instability and multiple tumor types; sustained Mad2 is unnecessary for maintenance.", "[49] Mad2-mediated chromosome instability increases Kras-independent relapse after initial regression on oncogene withdrawal.", "[50] Malignant teratocarcinoma cells contribute to functional normal tissues and germline after blastocyst incorporation.", "[51] Interrupted in vivo reprogramming induces dysplastic tumors, and tumor-derived iPSCs can form nonneoplastic kidney cells.", "[52] IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres.", "[53] Rare melanoma transcriptional states predict resistance and drug-induced reprogramming stabilizes it.", "[54] Single-clone cancer cultures yield reversible persisters; KDM5A depletion reduces tolerance without detectable parental proliferation loss.", "[55] Therapy induces APOBEC3A in persisters; deletion reduces mutations/structural changes and delays resistance, with concordant patient signatures.", "[56] T790M resistance emerges through either pre-existing clones or evolution from tolerant cells; apoptosis-targeted treatment restores sensitivity in a subset.", "[58] Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition.", "[59] 1106-person IRIS randomization improves cytogenetic response and freedom from blast/accelerated progression with BCR-ABL-directed imatinib.", "[61] IMADGIST randomizes 136 high-risk resected GIST patients after three years of imatinib; continuation improves disease-free survival.", "[62] 556-person FLAURA compares EGFR inhibitors and improves PFS with osimertinib in defined sensitizing mutations.", "[63] Planned FLAURA secondary survival analysis favors osimertinib, median 38.6 versus 31.8 months.", "[64] 682-person ADAURA adjuvant randomization improves overall survival after EGFR-mutant lung-cancer resection, with or without prior chemotherapy.", "[65] 303-person ALEX improves PFS and CNS progression with alectinib versus crizotinib in ALK-positive lung cancer.", "[66] LIBRETTO-431 compares selective RET inhibition with chemotherapy with/without pembrolizumab and improves PFS in fusion-positive lung cancer.", "[67] 675-person BRIM3 improves survival and PFS with vemurafenib versus dacarbazine in BRAF V600E melanoma.", "[68] 704-person COMBI-v improves overall survival with BRAF/MEK combination versus vemurafenib in BRAF V600 melanoma.", "[69] 345-person CodeBreaK200 improves PFS with sotorasib versus docetaxel in previously treated KRAS G12C lung cancer.", "[70] 291-person LIBRETTO-531 improves PFS with selective RET inhibition versus multikinase inhibitors in RET-mutant medullary thyroid cancer." ], "what_would_cross_it": "In representative predeclared histologies, compare mutation loss/correction and matched restoration with tissue/state interventions while controlling mutation burden and exposure; establish dominant mediation of both initiation and sustained cancer behavior." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Normal mutant tissue compared with cancers and gene-specific normal-versus-malignant fitness.", "Inert-cutting/non-targeting sgRNAs, Cas9-negative cohorts and oncogenic allele contrasts.", "Endogenous p53 restoration with normal-tissue observations.", "APC off/on/re-suppression, lineage re-label and Kras/p53 persistence.", "Single-clone tolerant-state generation, quiescence controls and parental proliferation after KDM5A loss.", "PM-versus-PBS genome burden and concomitant anti-IL1beta versus control antibody.", "Polycomb recovery, multiple perturbations, control genomes and variant thresholds.", "Fibroblast depletion across genetic backgrounds and partial immune rescue, retaining reduced survival despite lower tumor weight.", "Clinical overall survival versus PFS, crossover, same-trial follow-up and genotype selection." ], "note": "Cancer classes differ in point mutations, copy number, rearrangements, lineage and developmental state. Genotype-defined causal dependencies are not generalized from organoid or xenograft alone. Mutation presence, cellular fitness, initiation, maintenance and relapse are kept distinct. Normal mutants show insufficiency, not noncausality. IDH epigenetic mediation and genetically driven niche remodeling are compatible integrated mechanisms. Rare fly or forced reprogramming models do not estimate mutation-independent human cancer frequency; RET medullary thyroid cohorts may include germline alterations." }, "falsification_patterns_met": [ { "pattern": "Driver presence is not sufficient for malignancy", "evidence": "Multiple normal-tissue genomes and protective competitive clones contradict an automatic mutant-cell-equals-cancer rule, which is stronger than multistep genetic causality.", "downgrade_applied": false }, { "pattern": "Initiation and maintenance dependencies can differ", "evidence": "Transient Polycomb or Mad2 perturbation, MYC tissue-specific memory and culture/transplant Kras escape contrast with native APC/p53 restoration.", "downgrade_applied": false }, { "pattern": "Context is not uniformly tumor-promoting", "evidence": "Fibroblast depletion can worsen survival, and normal mutant neighbors eliminate nascent tumors.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Mutation defined only as a point substitution", "where": "Pediatric structural drivers, ALK/RET fusions, chromosome instability and biallelic loss." }, { "pitfall": "Benign mutant clones treated as refutation of multistep genetic causality", "where": "Normal skin/esophagus/endometrium and blood." }, { "pitfall": "Epigenetic mediation called independent mutation-free cause", "where": "IDH, APC/NOTUM, mutated lung substrate and therapy-induced APOBEC." }, { "pitfall": "Reversible state taken as proof of zero DNA lesions", "where": "Historical teratocarcinoma and interrupted reprogramming." }, { "pitfall": "Cultured doxycycline-independent relapse (Kras* reactivated) merged with native model", "where": "Original PMID23226501 distinguishes arms." }, { "pitfall": "Provider retrieval gap treated as scientific absence", "where": "Four of six targeted Consensus papers were not matched; original sources cover several of them." } ], "causal_tally_audit": { "tally_claimed_by_document": 50, "tally_after_audit": 50, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Shared cohorts, experimental platforms, transgenic lineages and repeated outcomes do not constitute fully independent causal lines." ] }, "steelman": { "case_one_rung_higher": "The strongest Ζ case combines widespread tumor driver selection, endogenous genetic initiation/maintenance, matched APC/p53 restoration, resistance mutations and large clinical survival benefits. This substantially reduces passenger-only and universal tissue-first explanations. It should reach Η for defined dependency and must not be pushed back to Γ. For broad sequential dominance at all stages, however, the selected causal contexts do not provide a representative genetic-versus-state comparison; real alternatives and stage-specific escape remain consequential rather than minor exceptions.", "case_one_rung_lower": "The strongest Δ case argues that broad exceptions leave only a single contribution experiment. That understates reproducible context-specific causal validity across pancreas, lung, colorectal, lymphoid and genotype-selected clinical disease. Explicitly bounded causality reaches Ε for the nominal broad claim; it is not merely a plausible cultured mechanism.", "which_rejected": "Reject Δ because many context-specific causal dependencies are established, and reject Ζ for the broad nominal primacy gate because representative cross-stage dominance is not demonstrated. Preserve SC1 Ζ and SC2 Η without importing them into SC3 or treating the remaining gap as refutation.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Across predeclared representative histologies, use lineage-resolved native cancers with selective driver correction/restoration and factorial niche/chromatin perturbations, preserving viability and measuring both early initiation and established maintenance/relapse." }, "final_score": { "hsef_level": "Ε", "hsef_descriptor": "Context-specific causality established", "confidence": "Moderate", "confidence_rationale": "70 primary reports with 8 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered scope-matched SC3 gate returns Ε: causal validity with explicit context limits. Driver identification reaches Ζ and defined initiation/maintenance dependencies reach Η through endogenous autochthonous genetics, restoration/rechallenge, human genomic natural history and genotype-selected hard clinical outcomes. The set is not re-capped by culture or xenograft limitations. Broad primacy requires a representative comparison of mutation, tissue and cell-state causation across initiation, maintenance and relapse; that burden is not established by genetic relevance alone. Benign driver clones challenge sufficiency, not the strong causal genetic evidence." }, "role_of_mechanism": { "classification": "primary driver", "derivation_step_matched": 3, "derivation": "In established genotype-defined cancers, engaging drivers initiates native tumors, removing/restoring causal driver function blocks or substantially delays malignant growth, and temporal on/off activity controls progression. Primary-driver status is supported within these tested settings, including APC, p53/Kras and genotype-dependent clinical cancers. It is not a declaration of universal primacy for every histology, initiation route or relapse state. The broad Ε score and the role answer different questions.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Recent multiplex autochthonous editing, transient Polycomb initiation, APOBEC perturbation and organoid evolution refine specified causal routes; this assembled corpus does not identify an ongoing representative pan-cancer mutation-versus-tissue trial crossing SC3.", "justification": "Recent multiplex autochthonous editing, transient Polycomb initiation, APOBEC perturbation and organoid evolution refine specified causal routes; this assembled corpus does not identify an ongoing representative pan-cancer mutation-versus-tissue trial crossing SC3." }, "stability": { "value": "Stable", "trigger": "No verified pending representative comparison is claimed to change the broad primacy grade imminently.", "justification": "No verified pending representative comparison is claimed to change the broad primacy grade imminently." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Ε", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Ε", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Across predeclared representative histologies, use lineage-resolved native cancers with selective driver correction/restoration and factorial niche/chromatin perturbations, preserving viability and measuring both early initiation and established maintenance/relapse.", "readout": "Native malignant incidence, longitudinal tumor burden, lineage persistence, metastasis, survival and recurrence with allele-sensitive genome/state monitoring", "critical_control": "Matched passenger editing, inactive perturbation, normal mutant clones, unchanged baseline viability, tissue lineage and restoration of the specific driver versus matched state rescue", "supporting_result": "Driver loss/correction suppresses initiation and sustained malignancy across contexts, matched restoration rescues it, and residual tissue/state effects account for only bounded exceptions", "falsifying_result": "Verified driver correction leaves sustained malignancy in representative native contexts, or genotype-matched initiation depends dominantly on a separable tissue/state perturbation despite the same genetic state" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Distinguish selected normal-clone fitness from malignant-driver function with matched normal/tumor lineage perturbations.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Compare mutation and tissue/state causation factorially across representative predeclared histologies; avoid responder-defined scope.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Test initiation and maintenance separately, retaining residual cells and relapse rather than equating regression with eradication.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Determine mutation-independent human cancer frequency with sensitive whole-genome/structural profiling and native functional tests; rare engineered examples cannot estimate prevalence.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Validate precise driver correction/restoration alongside pathway drugs to separate genotype dependency, off-target efficacy and incomplete engagement.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Track therapy-tolerant regulatory states into acquired genetic and nongenetic relapse, with longitudinal allele/state resolution.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Resolve niche-mediated genetic causality and context-specific stromal restraint instead of assuming competing models are mutually exclusive.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-06", "reviewer": "Codex", "evidence_base_note": "70 primary reports; literature cutoff 2026-10-06; source examination UTC date 2026-10-06; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Endogenous genetic natural experiments, APC loss/restoration/rechallenge, oncogene withdrawal and independent genotype-selected hard clinical outcomes were explicitly considered and carry SC2 to Η. No randomized trial of spontaneous mutation acquisition is required. These are not re-capped as a set. They do not establish mutation dominance over tissue/state causes across representative histologies at every cancer stage; this is the missing broad SC3 gate, not an absence of genetic causality." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Endogenous genetic natural experiments, APC loss/restoration/rechallenge, oncogene withdrawal and independent genotype-selected hard clinical outcomes were explicitly considered and carry SC2 to Η. No randomized trial of spontaneous mutation acquisition is required. These are not re-capped as a set. They do not establish mutation dominance over tissue/state causes across representative histologies at every cancer stage; this is the missing broad SC3 gate, not an absence of genetic causality." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Endogenous genetic natural experiments, APC loss/restoration/rechallenge, oncogene withdrawal and independent genotype-selected hard clinical outcomes were explicitly considered and carry SC2 to Η. No randomized trial of spontaneous mutation acquisition is required. These are not re-capped as a set. They do not establish mutation dominance over tissue/state causes across representative histologies at every cancer stage; this is the missing broad SC3 gate, not an absence of genetic causality." }, { "kind": "withdrawal_rechallenge", "available": true, "why_not_sufficient": "Endogenous genetic natural experiments, APC loss/restoration/rechallenge, oncogene withdrawal and independent genotype-selected hard clinical outcomes were explicitly considered and carry SC2 to Η. No randomized trial of spontaneous mutation acquisition is required. These are not re-capped as a set. They do not establish mutation dominance over tissue/state causes across representative histologies at every cancer stage; this is the missing broad SC3 gate, not an absence of genetic causality." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Endogenous genetic natural experiments, APC loss/restoration/rechallenge, oncogene withdrawal and independent genotype-selected hard clinical outcomes were explicitly considered and carry SC2 to Η. No randomized trial of spontaneous mutation acquisition is required. These are not re-capped as a set. They do not establish mutation dominance over tissue/state causes across representative histologies at every cancer stage; this is the missing broad SC3 gate, not an absence of genetic causality." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 70, "claims_total": 74, "claims_verified": 74, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 70, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Original observations on 48 retinoblastoma cases and age/multiplicity statistics support a two-event model distinguishing inherited and sporadic disease. Historical statistical inference does not directly identify the mutations or establish maintenance dependence; the inherited first event is not somatic.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C2", "text": "Across 172 colorectal neoplasms, RAS mutation and chromosome losses accumulate with pathological progression. Cross-sectional stages do not directly trace a single lineage or prove a universal obligatory order or ongoing dependency.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C3", "text": "Deep sequencing of 234 normal skin biopsies from four people finds strong selection of cancer-associated genes while epidermal function is maintained. Driver presence and competitive fitness are not equivalent to malignant sufficiency; benign clones do not refute later cooperative genetic causality.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C4", "text": "Whole genomes from normal crypts of 42 individuals reveal mutational processes and probable drivers in around 1 percent of middle-aged crypts. Normal mutant crypts are not inevitable precursors; acquisition alone does not establish cancer or maintenance.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C5", "text": "Selection analysis of 7664 tumors across 29 types distinguishes positively selected coding variants and context-dependent driver burdens. Statistical selection is not matched functional validation of every variant; coding substitution counts omit other genetic classes. Linked erratum metadata is retained.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C6", "text": "Whole genomes from 632 normal bronchial colonies link smoking to mutation burden and drivers; lower-burden cells are more frequent after cessation. Sixteen subjects and normal-cell expansion do not directly estimate cancer prevention mediation; carcinogenic promotion can accompany mutagenesis.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C7", "text": "2520 metastatic tumor-normal genome pairs show predominantly clonal drivers, frequent genome duplication and biallelic suppressor inactivation. Genomic prevalence and proposed actionability are not experimental necessity or successful treatment of each lesion.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C8", "text": "1699 pediatric cancers reveal driver genes distinct from adult disease and a majority of alteration events as copy-number or structural changes. Restricting mutation to point substitutions would misrepresent this genetic evidence; six histotypes do not establish pan-cancer primacy by perturbation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C9", "text": "TCGA analysis of 3281 tumors across 12 types identifies significantly mutated genes, pathways and inferred clonal timing. Significance and survival associations cannot establish every alteration as functional or define an obligatory cancer sequence.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C10", "text": "NanoSeq profiles 1042 oral and 371 blood samples, detecting many selected clones with high sequencing specificity. Population-scale clonal fitness is not malignant sufficiency or progression necessity; these normal tissues are not independent cancer interventions.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C11", "text": "Matched normal-adjacent and breast-tumor genome/epigenome profiles from 43 people reveal shared and divergent evolutionary histories. Adjacent tissue and inferred phylogenies cannot alone prove nongenetic initiation or distinguish all tumor-host directions.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C12", "text": "Normal esophagus has abundant positively selected NOTCH1 and TP53 clones; NOTCH1 alterations are more prevalent in normal tissue than cancer. Original sections distinguish approximate allele-fraction-derived cell coverage from independent mutations, and contrast TP53 enrichment in tumors. Normal fitness does not negate genotype-specific cancer dependencies.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Detection of mutations in normal esophagus, 2:Colonization of the epithelium by NOTCH1-mutant clones. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C13", "text": "682 normal esophageal samples show age/lifestyle-associated expansion and overrepresentation of some driver genes relative to cancer. Cross-sectional remodelling is not direct malignant-lineage tracking; gene-specific fitness differs between normal and cancer tissue.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C14", "text": "Longitudinal tracking of 697 hematopoietic clones in 385 people links genotype-specific growth and malignant progression risk. Risk enrichment and growth are not deterministic malignancy; age and competitive context condition the same mutation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C15", "text": "Endogenous mouse esophageal carcinogenesis and competitive-clone induction/inhibition show mutant neighboring epithelium can eliminate nascent tumors. Competition is a causal tissue modifier with retained mutant neoplasms, not proof that genetic lesions are dispensable across cancer.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C16", "text": "1311 normal endometrial glands reveal rhizome-linked clonal expansion and early copy-neutral loss of heterozygosity persisting in normal tissue. Clonal architecture and tolerated alterations are not cancer sufficiency; mutations include structural/allelic events beyond point substitutions.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C17", "text": "1737 normal biopsies across nine organs from five donors show tissue-dependent mutational accumulation and clonal architecture. Spatial restriction and morphology do not exclude occult precursor states or establish a genetic-versus-tissue causal hierarchy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C18", "text": "Normal endometrial genomes contain driver-bearing clones acquired early and expanded with age, with lower burdens than cancers. Many normal driver-bearing glands never become malignant; driver presence alone is insufficient but can precede cooperative cancer evolution.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C19", "text": "Oncogenic RAS induces arrest in primary cells; p53/p16 inactivation or E1A permits bypass in defined species and cell systems. Forced expression and cell culture establish a cooperative checkpoint, not endogenous pan-cancer necessity or a universal mutation sequence.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C20", "text": "Barcoded autochthonous lung editing across KRAS G12C/G12D, BRAF and EGFR contexts shows causal suppressor effects can reverse sign. Original Results include inert-cutting and Cas9-negative controls and separate clone number from growth. Four lung contexts do not represent all histologies; mutation frequency alone predicts some functional effects poorly.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph3, 1:Results:paragraph4, 1:Results:paragraph18, 1:Results:paragraph19, 1:Results:paragraph20, 1:Results:paragraph21, 1:Results:paragraph24, 1:Results:paragraph28. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C21", "text": "Apc-mutant cells secrete NOTUM; genetic or pharmacological inhibition reduces wild-type competition loss, mutant fixation and adenomas. This is genetic causality mediated through the niche, not a competing mutation-free account; prevention of adenomas is not universal invasive-cancer maintenance.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C22", "text": "Restoring endogenous p53 regresses autochthonous lymphomas and sarcomas with different apoptosis/senescence responses and no detected normal-tissue injury. Defined p53-dependent models establish maintenance causality; they do not show every tumor is dependent or replace initiation with maintenance. Original body unavailable here.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C23", "text": "Endogenous Kras G12D and Trp53 R172H cooperate to generate invasive, metastatic pancreatic cancer with genomic instability. Prespecified engineered alleles show joint sufficiency in this tissue, not a universal sequence or mutation-only explanation of tissue context.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C24", "text": "Physiological mutant Kras expression induces the PanIN spectrum, with low-frequency spontaneous invasive/metastatic progression. Initiation is genetically imposed and pancreatic-lineage-specific; additional evolution and microenvironmental conditions remain.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C25", "text": "Conditional endogenous oncogenic Kras permits timed autochthonous lung tumor induction and progression analysis. Cre induction supplies the initiating alteration; no mutation-loss maintenance test or broad histological generalization follows from this report alone.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C26", "text": "Inducible pancreatic Kras withdrawal regresses primary and metastatic tumors; reactivation rapidly restores disease. Original Results show TetO-Kras with endogenous mutant p53 and induced pancreatitis. Off-doxy relapse occurs after culture/transplantation, not in the autochthonous mice; do not conflate those arms or call Kras endogenous expression.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph19, 1:Results:paragraph20, 1:Results:paragraph22, 1:Results:paragraph24, 1:Results:paragraph26, 1:Results:paragraph29. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C27", "text": "Conditional oncogenic Kras from its endogenous promoter causes fully penetrant myeloproliferation but not transplantable AML. A disease precursor dependency is not AML sufficiency, supporting genetic cooperation and lineage boundaries.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C28", "text": "Reversible pancreas-specific Kras expression induces and maintains lesions, with withdrawal causing regression and changes in fibroinflammatory stroma. Transgenic activation and tissue damage condition initiation; stromal mediation can be downstream of a causal mutation rather than an exclusive alternative.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C29", "text": "Conditional MYC expression produces hematologic malignancies that regress after transgene inactivation, with differentiation and restored hematopoiesis. Forced oncogene expression without endogenous mutation correction narrows interpretation to the induced dependency.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C30", "text": "MYC-off liver tumors differentiate and become dormant; reactivation restores malignancy with the same comparative-genomic signature. Reversal changes driver activity rather than eliminating every mutation; latent tumor identity and tissue-specific responses constrain permanent cure claims.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C31", "text": "Inducible pancreatic MYC tumors regress after inactivation but residual cells rapidly recur on re-expression. Marker-positive residual cells are not proof of a universal stem hierarchy; transgene-driven maintenance does not establish natural mutation primacy.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C32", "text": "Brief MYC inactivation produces sustained osteogenic tumor regression; reactivation induces apoptosis instead of recurrence. Tissue-specific epigenetic memory modifies response to the same driver; induced expression and inferred epigenetic mechanism limit universal conclusions.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C33", "text": "CD4 and thrombospondin functional contrasts show immune remodelling is required for sustained regression after MYC/BCR-ABL inactivation. Oncogene withdrawal and immune context cooperate; immune necessity does not negate genetic dependence. Linked erratum lacks a supplied PMID and details remain unexamined.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C34", "text": "Sequential APC/TP53/KRAS/SMAD4 editing produces niche-independent human organoids and invasive xenograft tumors. Culture selection and xenotransplantation alone do not establish endogenous human cancer dependency; engineered order is not proof of obligatory order.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C35", "text": "Isogenic five-pathway mutant organoids form tumors but fail liver macrometastatic colonization, unlike chromosome-unstable adenoma-derived organoids. Driver edits support causal sufficiency in the tested niche; invasion/metastasis requires additional lesions or context and is not fully reproduced.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C36", "text": "Orthotopic engineered organoids show mutation accumulation supports metastasis; specific niche signals restore growth when one oncogenic alteration is absent. Transplantation and niche rescue are bounded model evidence, not proof of mutation dispensability in all spontaneous cancers.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C37", "text": "MMR-deficient organoids acquire spontaneous pathway mutations under sequential niche-factor withdrawal and form xenograft tumors. Repair-defective background and designed selection are not ordinary in vivo initiation; spontaneous acquisition does not remove culture/transplant limits.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C38", "text": "Isogenic and patient-derived colorectal organoids link driver combinations to differentiation-dependent signaling and transcription. Single-cell maps and state associations do not isolate organismal necessity; differentiation coupling can coexist with genetic causality.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C39", "text": "Endogenous APC protein restoration reverses autochthonous colorectal adenomas/carcinomas, including Kras/p53-altered settings, with lineage-marked normal crypt behavior. Original Results show reversible shRNA loss rather than precise mutation repair, small Kras/p53 groups, residual microadenomas and repeat regrowth on APC re-silencing; this is powerful defined dependency, not permanent eradication of all mutant cells.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph13, 1:Results:paragraph14, 1:Results:paragraph15, 1:Results:paragraph16. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C40", "text": "Transient endogenous Polycomb depletion induces persistent native fly neoplasia after protein recovery; serial allografts grow and metastasize. Original Results/Methods test four controls and 12 tumors with pooled whole-genome data, no recurrent drivers and variant/allele-fraction thresholds. This does not prove zero sequence changes or ordinary human mutation-free prevalence; transplantation is not its only initiation evidence.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Epigenetic perturbations initiate tumours:paragraph0, 1:Epigenetic perturbations initiate tumours:paragraph2, 1:Epigenetic perturbations initiate tumours:paragraph3, 1:Epigenetic perturbations initiate tumours:paragraph4, 1:Epigenetic perturbations initiate tumours:paragraph5, 6:EICs are autonomous immortal tumours:paragraph0, 6:EICs are autonomous immortal tumours:paragraph1, 8:Methods:paragraph19, 8:Methods:paragraph29, 8:Methods:paragraph30. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C41", "text": "Matrix stiffness, integrin/Rho/ERK manipulations and contractility reduction alter malignant architecture in an integrated signaling circuit. In vitro phenotype reversion is not pan-cancer initiation or survival causality and does not remove the transformed genotype.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C42", "text": "Genetic depletion of proliferating alphaSMA fibroblasts accelerates pancreatic cancer and worsens survival; anti-CTLA4 partially rescues the altered state. Original Results replicate genetic backgrounds and retain poorer survival despite lower tumor weight, with pulmonary emboli and immune changes; stroma can restrain rather than uniformly promote cancer.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C43", "text": "Rat mammary stroma age/parity changes tumor incidence and permits normal ducts containing a tumor-origin RAS marker. Transplantation and host developmental/reproductive differences do not establish a universal tissue-first origin; persistent RAS marker supports genotype–phenotype separation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C44", "text": "Brief compression induces normal-like malignant breast structures; nitric-oxide inhibition blocks the architectural response. Three-dimensional morphology is not verified spontaneous cancer elimination or survival; altered context does not erase genomic lesions.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C45", "text": "Beta1-integrin inhibitory antibody/Fab reverses malignant breast architecture and reduces nude-mouse tumor formation; stimulatory antibody fails. Reversion is reversible on antibody removal; transplant/culture evidence supports contextual phenotype control but not tissue primacy across endogenous cancers.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C46", "text": "PM2.5 promotes EGFR/KRAS-mutant lung lesions; macrophage/IL1beta experiments connect inflammatory promotion to altered epithelial state. Original Results show pre-existing engineered drivers, short-term PM-versus-PBS genome comparisons and concomitant antibody suppression. This is nonmutagenic promotion in a mutant substrate, not proof that mutations are unnecessary.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:PM-mediated promotion of lung cancer:paragraph0, 1:PM-mediated promotion of lung cancer:paragraph1, 3:PM induces IL-1β production from macrophages. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C47", "text": "Rat recombination contrasts place NMU-associated mammary tumor initiation with exposed stroma, independent of epithelial exposure; Ha-ras status does not track all tumors. Different compartment exposure protocols, transplantation and one-gene mutation testing do not establish absence of other drivers or pan-cancer tissue-first necessity.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C48", "text": "Transient Mad2 overexpression induces chromosome instability and multiple tumor types; sustained Mad2 is unnecessary for maintenance. Chromosome gains/losses are genetic alterations; forced checkpoint expression is not an endogenous mutation-free origin or universal CIN-first model.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C49", "text": "Mad2-mediated chromosome instability increases Kras-independent relapse after initial regression on oncogene withdrawal. Engineered chromosome instability and varied relapse pathways support a context, not all cancers or absence of genetic evolution.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C50", "text": "Malignant teratocarcinoma cells contribute to functional normal tissues and germline after blastocyst incorporation. Modal chromosome number and strain markers are not modern genome-wide driver exclusion; rare embryonic reprogramming cannot estimate ordinary adult cancer prevalence.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C51", "text": "Interrupted in vivo reprogramming induces dysplastic tumors, and tumor-derived iPSCs can form nonneoplastic kidney cells. Forced reprogramming and developmental reset demonstrate context-specific epigenetic plasticity; reversibility is not sensitive genome-wide proof of zero mutations or broad human predominance.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C52", "text": "IDH-mutant glioma insulation is altered; demethylation partly restores regulation and CTCF-site disruption activates PDGFRA in wild-type-IDH spheres. Mutation-to-epigenetic causation is an integrated mechanism, not an independent refutation of mutations. Gliomasphere proliferation is not complete in vivo cancer dependency.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C53", "text": "Rare melanoma transcriptional states predict resistance and drug-induced reprogramming stabilizes it. Resistance-state plasticity does not establish nongenetic original initiation; no clear genetic cause is not exhaustive exclusion. Linked correction details are qualified.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C54", "text": "Single-clone cancer cultures yield reversible persisters; KDM5A depletion reduces tolerance without detectable parental proliferation loss. Original Results distinguish nine-doubling persister reversal from roughly 90-doubling expanded-persistor reversal and CD133/quiescence controls. These cells retain cancer-driving mutations; clinical relapse necessity is not directly tested.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C55", "text": "Therapy induces APOBEC3A in persisters; deletion reduces mutations/structural changes and delays resistance, with concordant patient signatures. Genetic evolution can arise from a nongenetic persister state; patient signatures and cell models do not prove every resistance lineage follows this route.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C56", "text": "T790M resistance emerges through either pre-existing clones or evolution from tolerant cells; apoptosis-targeted treatment restores sensitivity in a subset. Patient-derived culture convergence supports distinct paths, not a single universal sequence or permanent dependence on the original inhibitor target.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C57", "text": "Biopsies from 37 resistant EGFR-mutant lung cancers retain original drivers but show additional genetic or histological changes, including small-cell transition. Retained driver presence does not prove retained dependency; serial samples are selected resistant cases and not randomized mechanism perturbations.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C58", "text": "Serial patient RET resistance variants converge at solvent-front G810, with xenograft and enzyme/cell assays confirming loss of inhibition. Small selected resistance series, shared pathway inhibitors and xenografts do not quantify pan-cancer mutation primacy or exclude state-based escape.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C59", "text": "1106-person IRIS randomization improves cytogenetic response and freedom from blast/accelerated progression with BCR-ABL-directed imatinib. Drug effects are pathway perturbation rather than correction of the chromosome fusion; crossover and additional kinase targets limit isolated genetic mediation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C60", "text": "IRIS long-term follow-up reports sustained imatinib efficacy and 83.3 percent estimated ten-year survival. Same original randomized cohort; heavy crossover means this survival estimate is not an independent randomized survival comparison or cure of every stem cell.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C61", "text": "IMADGIST randomizes 136 high-risk resected GIST patients after three years of imatinib; continuation improves disease-free survival. No survival difference is demonstrated; treatment-selected GIST and KIT/PDGFRA pathway targeting do not generalize to all tumors or establish mutation order.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C62", "text": "556-person FLAURA compares EGFR inhibitors and improves PFS with osimertinib in defined sensitizing mutations. Both arms inhibit EGFR, so comparative efficacy also reflects drug properties; interim overall survival did not meet its statistical boundary.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C63", "text": "Planned FLAURA secondary survival analysis favors osimertinib, median 38.6 versus 31.8 months. Same FLAURA patients, not a separate replication; more effective genotype-matched drugs support dependency without proving unselected pan-cancer dominance.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C64", "text": "682-person ADAURA adjuvant randomization improves overall survival after EGFR-mutant lung-cancer resection, with or without prior chemotherapy. Defined stages and mutations plus surgery constrain scope; therapeutic consequence does not directly establish spontaneous initiation or universal sufficiency.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C65", "text": "303-person ALEX improves PFS and CNS progression with alectinib versus crizotinib in ALK-positive lung cancer. Both arms target ALK; pharmacology and CNS penetration differ, and initial report does not establish overall-survival benefit or universal ALK dependence.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C66", "text": "LIBRETTO-431 compares selective RET inhibition with chemotherapy with/without pembrolizumab and improves PFS in fusion-positive lung cancer. A structural rearrangement is genetic driver evidence; selected advanced disease and immature/crossover survival do not establish all-cancer primacy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C67", "text": "675-person BRIM3 improves survival and PFS with vemurafenib versus dacarbazine in BRAF V600E melanoma. Clinical selection and eventual resistance constrain durability; target inhibition does not correct every mutation or remove tissue/immune mediation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 67 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C68", "text": "704-person COMBI-v improves overall survival with BRAF/MEK combination versus vemurafenib in BRAF V600 melanoma. A downstream combination strengthens consequence and resistance control, not mutation-only origin; distinct from BRIM3 despite related drug pathway.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 68 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C69", "text": "345-person CodeBreaK200 improves PFS with sotorasib versus docetaxel in previously treated KRAS G12C lung cancer. The benefit is modest and this abstract does not establish overall-survival benefit; mutation-specific dependence varies by disease and treatment stage.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 69 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C70", "text": "291-person LIBRETTO-531 improves PFS with selective RET inhibition versus multikinase inhibitors in RET-mutant medullary thyroid cancer. RET alterations may be inherited or somatic; this cohort cannot be counted as a purely somatic initiating-mutation experiment. Both arms target RET-pathway activity.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 70 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC1", "text": "Recurrent alterations are distinguished from passengers by selection, clonal timing and precise functional perturbations in specific histologies. Independent genome platforms and autochthonous editing reduce sequencing-error and correlation-only explanations. Genomic annotation alone remains insufficient, and fitness in normal tissue is not necessarily cancer-driving fitness. Ζ is supported across assay classes; most claimed variant classes have not individually received therapeutic/endogenous confirmation, so Η is not assigned to every driver-identification inference.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 20, 34, 35, 37, 38, 52, 57, 58 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC2", "text": "Endogenous Kras combinations, endogenous p53 restoration, reversible APC loss/restoration and lineage-marked tumor differentiation establish causal dependencies in defined cancers. Multiple genotype-selected clinical trials yield progression or survival consequences across EGFR, BRAF, RET, ALK and BCR-ABL settings. These complementary lines fail differently and satisfy Η in the prespecified genotype-defined scope. The subclaim is initiation OR maintenance, not a requirement that each report establish both. Residual states, relapse and incomplete target response prevent Θ/Ω for most cancer behavior or universal necessity/sufficiency.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 15, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC3", "text": "Genetic alterations are primary drivers in many tested cancers, with causal initiation and ongoing dependency, rather than mere passengers. Their phenotypic output depends on lineage, niche, immunity and chromatin; tissue mediation may be downstream of the genetic lesion and is not automatically an exclusive rival. Normal mutant tissues show insufficiency, fly/reprogramming models demonstrate bounded alternative initiation, and relapse can change dependence. Ε credits the real causal model while restricting the broad dominant-sequential initiating-and-sustaining claim. This is not a finding that common cancers generally lack driver mutations.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CH", "text": "Somatic drivers cause and sustain many genotype-defined cancers; sequential mutation primacy across all cancer behavior remains context-dependent.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 39, 22, 20, 64, 46, 40 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-06", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Knudson AG et al. Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America. 1971.", "tier": "A", "kind": "primary", "pmid": "5279523", "doi": "10.1073/pnas.68.4.820", "url": "https://pubmed.ncbi.nlm.nih.gov/5279523/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID5279523", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC3" ] }, { "n": 2, "citation": "Vogelstein B, Fearon ER, Hamilton SR et al. Genetic alterations during colorectal-tumor development. The New England journal of medicine. 1988.", "tier": "A", "kind": "primary", "pmid": "2841597", "doi": "10.1056/NEJM198809013190901", "url": "https://pubmed.ncbi.nlm.nih.gov/2841597/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID2841597", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC3" ] }, { "n": 3, "citation": "Martincorena I, Roshan A, Gerstung M et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science (New York, N.Y.). 2015.", "tier": "A", "kind": "human_tissue", "pmid": "25999502", "doi": "10.1126/science.aaa6806", "url": "https://pubmed.ncbi.nlm.nih.gov/25999502/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25999502", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC3" ] }, { "n": 4, "citation": "Lee-Six H, Olafsson S, Ellis P et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature. 2019.", "tier": "A", "kind": "primary", "pmid": "31645730", "doi": "10.1038/s41586-019-1672-7", "url": "https://pubmed.ncbi.nlm.nih.gov/31645730/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31645730", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC1", "CSC3" ] }, { "n": 5, "citation": "Martincorena I, Raine KM, Gerstung M et al. Universal Patterns of Selection in Cancer and Somatic Tissues. Cell. 2017.", "tier": "A", "kind": "human_tissue", "pmid": "29056346", "doi": "10.1016/j.cell.2017.09.042", "url": "https://pubmed.ncbi.nlm.nih.gov/29056346/", "status_flags": [ "ErratumIn: PMID29906452" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID29056346", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC1", "CSC3" ] }, { "n": 6, "citation": "Yoshida K, Gowers KHC, Lee-Six H et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature. 2020.", "tier": "A", "kind": "primary", "pmid": "31996850", "doi": "10.1038/s41586-020-1961-1", "url": "https://pubmed.ncbi.nlm.nih.gov/31996850/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31996850", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC1", "CSC3" ] }, { "n": 7, "citation": "Priestley P, Baber J, Lolkema MP et al. Pan-cancer whole-genome analyses of metastatic solid tumours. Nature. 2019.", "tier": "A", "kind": "primary", "pmid": "31645765", "doi": "10.1038/s41586-019-1689-y", "url": "https://pubmed.ncbi.nlm.nih.gov/31645765/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31645765", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC1", "CSC3" ] }, { "n": 8, "citation": "Ma X, Liu Y, Liu Y et al. Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature. 2018.", "tier": "A", "kind": "primary", "pmid": "29489755", "doi": "10.1038/nature25795", "url": "https://pubmed.ncbi.nlm.nih.gov/29489755/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID29489755", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC1", "CSC3" ] }, { "n": 9, "citation": "Kandoth C, McLellan MD, Vandin F et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013.", "tier": "A", "kind": "human_tissue", "pmid": "24132290", "doi": "10.1038/nature12634", "url": "https://pubmed.ncbi.nlm.nih.gov/24132290/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24132290", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1", "CSC3" ] }, { "n": 10, "citation": "Lawson ARJ, Abascal F, Nicola PA et al. Somatic mutation and selection at population scale. Nature. 2025.", "tier": "A", "kind": "primary", "pmid": "41062696", "doi": "10.1038/s41586-025-09584-w", "url": "https://pubmed.ncbi.nlm.nih.gov/41062696/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID41062696", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC1", "CSC3" ] }, { "n": 11, "citation": "Zhu B, Tapinos A, Koka H et al. Genomes and epigenomes of matched normal and tumor breast tissue reveal diverse evolutionary trajectories and tumor-host interactions. American journal of human genetics. 2024.", "tier": "A", "kind": "primary", "pmid": "39492056", "doi": "10.1016/j.ajhg.2024.10.005", "url": "https://pubmed.ncbi.nlm.nih.gov/39492056/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39492056", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC1", "CSC3" ] }, { "n": 12, "citation": "Martincorena I, Fowler JC, Wabik A et al. Somatic mutant clones colonize the human esophagus with age. Science (New York, N.Y.). 2018.", "tier": "A", "kind": "human_tissue", "pmid": "30337457", "doi": "10.1126/science.aau3879", "url": "https://pubmed.ncbi.nlm.nih.gov/30337457/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30337457", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Detection of mutations in normal esophagus, 2:Colonization of the epithelium by NOTCH1-mutant clones. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC1", "CSC3" ] }, { "n": 13, "citation": "Yokoyama A, Kakiuchi N, Yoshizato T et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature. 2019.", "tier": "A", "kind": "primary", "pmid": "30602793", "doi": "10.1038/s41586-018-0811-x", "url": "https://pubmed.ncbi.nlm.nih.gov/30602793/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30602793", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC1", "CSC3" ] }, { "n": 14, "citation": "Fabre MA, de Almeida JG, Fiorillo E et al. The longitudinal dynamics and natural history of clonal haematopoiesis. Nature. 2022.", "tier": "A", "kind": "primary", "pmid": "35650444", "doi": "10.1038/s41586-022-04785-z", "url": "https://pubmed.ncbi.nlm.nih.gov/35650444/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35650444", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC1", "CSC3" ] }, { "n": 15, "citation": "Colom B, Herms A, Hall MWJ et al. Mutant clones in normal epithelium outcompete and eliminate emerging tumours. Nature. 2021.", "tier": "A", "kind": "primary", "pmid": "34646013", "doi": "10.1038/s41586-021-03965-7", "url": "https://pubmed.ncbi.nlm.nih.gov/34646013/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34646013", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC2", "CSC3" ] }, { "n": 16, "citation": "Yamaguchi M, Nakaoka H, Suda K et al. Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium. Nature communications. 2022.", "tier": "A", "kind": "primary", "pmid": "35177608", "doi": "10.1038/s41467-022-28568-2", "url": "https://pubmed.ncbi.nlm.nih.gov/35177608/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35177608", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C16", "CSC1", "CSC3" ] }, { "n": 17, "citation": "Li R, Di L, Li J et al. A body map of somatic mutagenesis in morphologically normal human tissues. Nature. 2021.", "tier": "A", "kind": "primary", "pmid": "34433965", "doi": "10.1038/s41586-021-03836-1", "url": "https://pubmed.ncbi.nlm.nih.gov/34433965/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34433965", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC1", "CSC3" ] }, { "n": 18, "citation": "Moore L, Leongamornlert D, Coorens THH et al. The mutational landscape of normal human endometrial epithelium. Nature. 2020.", "tier": "A", "kind": "primary", "pmid": "32350471", "doi": "10.1038/s41586-020-2214-z", "url": "https://pubmed.ncbi.nlm.nih.gov/32350471/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32350471", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC1", "CSC3" ] }, { "n": 19, "citation": "Serrano M, Lin AW, McCurrach ME et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997.", "tier": "A", "kind": "primary", "pmid": "9054499", "doi": "10.1016/s0092-8674(00)81902-9", "url": "https://pubmed.ncbi.nlm.nih.gov/9054499/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID9054499", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC2", "CSC3" ] }, { "n": 20, "citation": "Blair LM, Juan JM, Sebastian L et al. Oncogenic context shapes the fitness landscape of tumor suppression. Nature communications. 2023.", "tier": "A", "kind": "primary", "pmid": "37828026", "doi": "10.1038/s41467-023-42156-y", "url": "https://pubmed.ncbi.nlm.nih.gov/37828026/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37828026", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph3, 1:Results:paragraph4, 1:Results:paragraph18, 1:Results:paragraph19, 1:Results:paragraph20, 1:Results:paragraph21, 1:Results:paragraph24, 1:Results:paragraph28. No complete-paper or supplement audit claimed.", "carries_claims": [ "C20", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 21, "citation": "Flanagan DJ, Pentinmikko N, Luopajärvi K et al. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature. 2021.", "tier": "A", "kind": "primary", "pmid": "34079124", "doi": "10.1038/s41586-021-03525-z", "url": "https://pubmed.ncbi.nlm.nih.gov/34079124/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34079124", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC2", "CSC3" ] }, { "n": 22, "citation": "Ventura A, Kirsch DG, McLaughlin ME et al. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007.", "tier": "A", "kind": "primary", "pmid": "17251932", "doi": "10.1038/nature05541", "url": "https://pubmed.ncbi.nlm.nih.gov/17251932/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID17251932", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C22", "CSC2", "CSC3", "CH" ] }, { "n": 23, "citation": "Hingorani SR, Wang L, Multani AS et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer cell. 2005.", "tier": "A", "kind": "primary", "pmid": "15894267", "doi": "10.1016/j.ccr.2005.04.023", "url": "https://pubmed.ncbi.nlm.nih.gov/15894267/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID15894267", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C23", "CSC2", "CSC3" ] }, { "n": 24, "citation": "Hingorani SR, Petricoin EF, Maitra A et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. 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