{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Cancer as Atavism", "entry_form": "phenomenon", "gradeable_restatement": "Cancer is the re-expression of a coherent, pre-existing ancestral pre-metazoan gene-regulatory program, and that program drives tumorigenesis.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Cancer type, lineage, endogenous versus installed regulator, growth rate, treatment state and preregistered ancestral network definition", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Cancer as Atavism", "central_claim": "Cancer is the re-expression of a coherent, pre-existing ancestral pre-metazoan gene-regulatory program, and that program drives tumorigenesis.", "proposed_mechanism": "Cancer is the re-expression of a coherent, pre-existing ancestral pre-metazoan gene-regulatory program, and that program drives tumorigenesis.", "claimed_scope": "The coherent pre-existing pre-metazoan regulatory program as a causal driver of initiation, maintenance and relapse, separated from evolutionary conservation, developmental reuse and flexible constraint-loss narratives.", "claimed_level": [ "initiation", "maintenance", "relapse" ], "is_conjunctive": true, "conjunctive_note": "Index names SC2 and SC3 as distinctive gates but its schema permits one primary ID. Register SC3 primacy as the main gate, with mandatory paired SC2/SC3 minimum and weakest-link sensitivities. Ancient-gene expression alone does not prove an executed program. Do not redefine partial atavism after outcomes." }, "rubric_routing": { "primary_rubric": "02-cancer-biology.md", "secondary_rubrics": [ "03-epigenetics-gene-regulation.md" ], "index_notes_applied": [ "Index names SC2 and SC3 as distinctive gates but its schema permits one primary ID. Register SC3 primacy as the main gate, with mandatory paired SC2/SC3 minimum and weakest-link sensitivities. Ancient-gene expression alone does not prove an executed program. Do not redefine partial atavism after outcomes." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Tumors overexpress ancient unicellular-origin genes and downregulate metazoan-origin genes.", "subclaim_type": "existence", "scope": "matched tumor/normal tissue and proliferative baselines", "claimed_scope": "matched tumor/normal tissue and proliferative baselines", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Phylostratigraphy with orthology/detection and mitotic-index controls", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Β: ancient-expression and coexpression patterns are human associations, with a real methods debate and incomplete matched-normal proliferation controls." }, { "id": "SC2", "statement": "The shift executes a coherent pre-existing ancestral program rather than loss of multicellular constraints.", "subclaim_type": "mechanism", "scope": "predeclared ancestral network across tumor contexts", "claimed_scope": "predeclared ancestral network across tumor contexts", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Program-specific perturbation/rescue against rival predictions", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Γ: network/mutation/dependency integration supplies mechanistic plausibility and culture perturbations, but not recovery, selective subtraction or rescue of a predeclared coherent ancestral program. New mixed modules favor rewiring." }, { "id": "SC3", "statement": "The ancestral program drives tumorigenesis rather than accompanies it.", "subclaim_type": "primacy", "scope": "endogenous initiation, maintenance and relapse", "claimed_scope": "endogenous initiation, maintenance and relapse", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Temporal and selective program subtraction/reconstitution", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Γ: functional regulator and metabolic dependencies exist, but no program-specific endogenous in vivo initiation/maintenance/relapse dependence establishes the nominal driver." }, { "id": "SC4", "statement": "Tumor metabolism regresses sequentially down the evolutionary timeline.", "subclaim_type": "generalization", "scope": "registered serial-atavism order across conditions", "claimed_scope": "registered serial-atavism order across conditions", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Longitudinal flux/isotope measurements testing ordered transitions", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Β: metabolic state associations are heterogeneous; retained oxidation and treatment-selected respiratory states constrain serial regression, and no registered longitudinal evolutionary order was tested." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "Index names SC2 and SC3 as distinctive gates but its schema permits one primary ID. Register SC3 primacy as the main gate, with mandatory paired SC2/SC3 minimum and weakest-link sensitivities. Ancient-gene expression alone does not prove an executed program. Do not redefine partial atavism after outcomes.", "primary_subclaim_id": "SC3", "aggregation_derivation": "Preregistered primary SC3 returns Γ. The mandatory paired SC2/SC3 minimum also returns Γ; weakest-link returns Β because SC1/SC4 remain associative, and scope-matched primacy returns Γ. The score concerns the distinctive coherent-program driver, not the proven existence of ancient genes or selected oncogene dependencies.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "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": "Somatic selection after disrupted multicellular constraints", "core_claim": "Selected regulators and loss of growth constraints cause context-specific tumors and recurrent escape.", "explains_what_nominal_does_not": "Selected regulators and loss of growth constraints cause context-specific tumors and recurrent escape.", "strongest_supporting_evidence": [ "MYC withdrawal/rechallenge across tissues, KRAS maintenance and bypass, and clonal selection: PMID10488335,12098700,15475948,22541435,24954535,37046096." ], "strongest_contradictory_evidence": [ "Conditional transgenes and overlapping investigative lineages limit generality; not a complete unified account of all human initiation." ], "hsef_level_for_this_model": "Ε", "rationale": "MYC withdrawal/rechallenge across tissues, KRAS maintenance and bypass, and clonal selection: PMID10488335,12098700,15475948,22541435,24954535,37046096. Conditional transgenes and overlapping investigative lineages limit generality; not a complete unified account of all human initiation." }, { "rank_in_tournament": 2, "model_id": "M4", "is_nominal": false, "name": "Forward ecological adaptation", "core_claim": "Tumors remodel regulatory and metabolic states in response to lineage, nutrients and treatment.", "explains_what_nominal_does_not": "Tumors remodel regulatory and metabolic states in response to lineage, nutrients and treatment.", "strongest_supporting_evidence": [ "New UC-MC modules, reversible integrin phenotype, in vivo GOT2 dispensability and respiratory residual states: PMID38685127,9105051,35815941,25119024." ], "strongest_contradictory_evidence": [ "Coexpression is not directionality, culture/xenografts are restricted, and the 2014 residual study has incompletely audited 2026 correction." ], "hsef_level_for_this_model": "Ε", "rationale": "New UC-MC modules, reversible integrin phenotype, in vivo GOT2 dispensability and respiratory residual states: PMID38685127,9105051,35815941,25119024. Coexpression is not directionality, culture/xenografts are restricted, and the 2014 residual study has incompletely audited 2026 correction." }, { "rank_in_tournament": 3, "model_id": "M3", "is_nominal": false, "name": "Proliferation and homology confounding", "core_claim": "Growth and gene-age inference can create part of the apparent ancient-state shift.", "explains_what_nominal_does_not": "Growth and gene-age inference can create part of the apparent ancient-state shift.", "strongest_supporting_evidence": [ "Growth-matched EGF/KRAS cells and direct methods benchmarks: PMID33811729,25312911,30060201." ], "strongest_contradictory_evidence": [ "Bias rebuttal PMID28087778 and some tumor-specific regulatory links remain; not demonstrated that every cancer age signature is artifact." ], "hsef_level_for_this_model": "Δ", "rationale": "Growth-matched EGF/KRAS cells and direct methods benchmarks: PMID33811729,25312911,30060201. Bias rebuttal PMID28087778 and some tumor-specific regulatory links remain; not demonstrated that every cancer age signature is artifact." }, { "rank_in_tournament": 4, "model_id": "M1", "is_nominal": true, "name": "Coherent ancestral program", "core_claim": "A preserved pre-metazoan regulatory module is re-executed and drives tumors.", "explains_what_nominal_does_not": "A preserved pre-metazoan regulatory module is re-executed and drives tumors.", "strongest_supporting_evidence": [ "Phylostratigraphic expression and gene-dependency integration: PMID28484005,30803482." ], "strongest_contradictory_evidence": [ "Novel mixed modules, lineage-specific dependencies and missing selective whole-program rescue leave the distinctive causal claim unresolved." ], "hsef_level_for_this_model": "Γ", "rationale": "Phylostratigraphic expression and gene-dependency integration: PMID28484005,30803482. Novel mixed modules, lineage-specific dependencies and missing selective whole-program rescue leave the distinctive causal claim unresolved." }, { "rank_in_tournament": 5, "model_id": "M5", "is_nominal": false, "name": "Serial metabolic atavism", "core_claim": "Tumors progress through a prescribed sequence of historically older metabolic states.", "explains_what_nominal_does_not": "Tumors progress through a prescribed sequence of historically older metabolic states.", "strongest_supporting_evidence": [ "Selected glycolytic/redox and ancient metabolic enrichments: PMID23535601,36499258." ], "strongest_contradictory_evidence": [ "Human oxidation, context-matched growth, oxidative residual/CLL/hepatoma states and absent registered longitudinal ordering: PMID26853473,28985563,33811729,28835371,10683245." ], "hsef_level_for_this_model": "Β", "rationale": "Selected glycolytic/redox and ancient metabolic enrichments: PMID23535601,36499258. Human oxidation, context-matched growth, oxidative residual/CLL/hepatoma states and absent registered longitudinal ordering: PMID26853473,28985563,33811729,28835371,10683245." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Lock an ancestral edge-defined network and competing selection/rewiring predictions before measurements; compare growth-matched normal and tumor lineages with selective network disruption and matched rescue while preserving basal replication.", "study_separating_rank1_from_rank2": "Lock an ancestral edge-defined network and competing selection/rewiring predictions before measurements; compare growth-matched normal and tumor lineages with selective network disruption and matched rescue while preserving basal replication.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "28484005", "title": "Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors.", "citation": "Trigos AS, Pearson RB, Papenfuss AT et al. Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors. Proceedings of the National Academy of Sciences of the United States of America. 2017.", "doi": "10.1073/pnas.1617743114", "pmcid": "PMC5474804", "url": "https://pubmed.ncbi.nlm.nih.gov/28484005/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28484005/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28484005", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph49, 0:Publisher HTML paragraphs:paragraph50. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human computational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Seven TCGA tumor types, 3473 tumors/386 normals and 17318 aged genes show UC-biased expression and disrupted UC-MC coexpression; twelve hub regulators are proposed.", "what_it_does_not_show": "Both normal and tumor tissue co-regulate ancient processes; not all UC processes rise. Bulk growth/composition and shared orthology assignments remain; no ancestral-program reconstitution.", "confounders_present": [ "Both normal and tumor tissue co-regulate ancient processes; not all UC processes rise. Bulk growth/composition and shared orthology assignments remain; no ancestral-program reconstitution." ], "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": "30803482", "title": "Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer.", "citation": "Trigos AS, Pearson RB, Papenfuss AT et al. Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer. eLife. 2019.", "doi": "10.7554/eLife.40947", "pmcid": "PMC6402835", "url": "https://pubmed.ncbi.nlm.nih.gov/30803482/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30803482/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30803482", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Materials and methods:paragraph0, 3:Materials and methods:paragraph1, 3:Materials and methods:paragraph11, 3:Materials and methods:paragraph12, 3:Materials and methods:paragraph16, 3:Materials and methods:paragraph25, 3:Materials and methods:paragraph27. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human computational with culture-screen integration", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Thirty solid cancer types connect mutation/CNA strata to UC-MC regulatory links; 364 Avana cell-line CRISPR screens and 250-drug data inform dependency/response associations.", "what_it_does_not_show": "There is genuine single-gene perturbation data, but no selective unified ancestral network subtraction/rescue or endogenous in vivo program dependency; pooled regulator contrasts are not randomized installation.", "confounders_present": [ "There is genuine single-gene perturbation data, but no selective unified ancestral network subtraction/rescue or endogenous in vivo program dependency; pooled regulator contrasts are not randomized installation." ], "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": "38685127", "title": "Disruption of metazoan gene regulatory networks in cancer alters the balance of co-expression between genes of unicellular and multicellular origins.", "citation": "Trigos AS, Bongiovanni F, Zhang Y et al. Disruption of metazoan gene regulatory networks in cancer alters the balance of co-expression between genes of unicellular and multicellular origins. Genome biology. 2024.", "doi": "10.1186/s13059-024-03247-1", "pmcid": "PMC11057133", "url": "https://pubmed.ncbi.nlm.nih.gov/38685127/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38685127/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID38685127", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph9, 1:Results:paragraph12, 1:Results:paragraph24, 1:Results:paragraph26, 1:Results:paragraph31. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human computational", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "31 cancer types and 16 matched-normal cohorts show novel mixed UC-MC WGCNA modules, CNA associations and grade/stage differences.", "what_it_does_not_show": "Coexpression is not directed regulation; novel combinations argue against a simply restored intact network but do not disprove every partial-atavism definition. LGG/GBM class contrasts are not observed individual progression.", "confounders_present": [ "Coexpression is not directed regulation; novel combinations argue against a simply restored intact network but do not disprove every partial-atavism definition. LGG/GBM class contrasts are not observed individual progression." ], "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": "22285198", "title": "Tumor malignancy is engaged to prokaryotic homolog toolbox.", "citation": "Fernandes J, Guedes PG, Lage CL et al. Tumor malignancy is engaged to prokaryotic homolog toolbox. Medical hypotheses. 2012.", "doi": "10.1016/j.mehy.2011.12.014", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/22285198/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22285198/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID22285198", "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" ], "favors_models": [], "evidence_class": "Weak", "system": "comparative sequence analysis", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Original homology analysis identifies a prokaryotic metabolic toolbox among cancer-related human proteins.", "what_it_does_not_show": "Conserved protein ancestry does not specify a preserved ancestral regulatory program or its causal role in tumors.", "confounders_present": [ "Conserved protein ancestry does not specify a preserved ancestral regulatory program or its causal role in tumors." ], "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": "36499258", "title": "The Transcriptome and Proteome Networks of Malignant Tumours Reveal Atavistic Attractors of Polyploidy-Related Asexual Reproduction.", "citation": "Vainshelbaum NM, Giuliani A, Salmina K et al. The Transcriptome and Proteome Networks of Malignant Tumours Reveal Atavistic Attractors of Polyploidy-Related Asexual Reproduction. International journal of molecular sciences. 2022.", "doi": "10.3390/ijms232314930", "pmcid": "PMC9736112", "url": "https://pubmed.ncbi.nlm.nih.gov/36499258/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36499258/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36499258", "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" ], "favors_models": [], "evidence_class": "Weak", "system": "human sequence and proteomic network", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Whole-genome-duplication analysis of 1474 genes and cancer proteomics finds ancient and later placentation/cancer-testis enrichments.", "what_it_does_not_show": "Mixed evolutionary origins and network annotation are compatible with selective reuse; neither causal program execution nor uniformly pre-metazoan identity follows.", "confounders_present": [ "Mixed evolutionary origins and network annotation are compatible with selective reuse; neither causal program execution nor uniformly pre-metazoan identity follows." ], "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": 6, "pmid": "25312911", "title": "Phylostratigraphic bias creates spurious patterns of genome evolution.", "citation": "Moyers BA, Zhang J et al. Phylostratigraphic bias creates spurious patterns of genome evolution. Molecular biology and evolution. 2015.", "doi": "10.1093/molbev/msu286", "pmcid": "PMC4271527", "url": "https://pubmed.ncbi.nlm.nih.gov/25312911/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25312911/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID27738272" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25312911", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "simulation methods comparator", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Simulations show homology-detection error can bias inferred gene ages and expression-age trends.", "what_it_does_not_show": "Synthetic detection bias does not show all cancer age patterns are artifacts; linked erratum PMID27738272 details were not accessible for examination.", "confounders_present": [ "Synthetic detection bias does not show all cancer age patterns are artifacts; linked erratum PMID27738272 details were not accessible for examination." ], "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": "28637261", "title": "Further Simulations and Analyses Demonstrate Open Problems of Phylostratigraphy.", "citation": "Moyers BA, Zhang J et al. Further Simulations and Analyses Demonstrate Open Problems of Phylostratigraphy. Genome biology and evolution. 2017.", "doi": "10.1093/gbe/evx109", "pmcid": "PMC5501971", "url": "https://pubmed.ncbi.nlm.nih.gov/28637261/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28637261/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28637261", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "simulation methods comparator", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Further simulations and empirical-method assessment identify systematic phylostratigraphic errors.", "what_it_does_not_show": "A disputed methodological result is not direct tumor causality evidence; robustness should be tested on the actual cancer gene sets.", "confounders_present": [ "A disputed methodological result is not direct tumor causality evidence; robustness should be tested on the actual cancer gene sets." ], "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": "28087778", "title": "No Evidence for Phylostratigraphic Bias Impacting Inferences on Patterns of Gene Emergence and Evolution.", "citation": "Domazet-Lošo T, Carvunis AR, Albà MM et al. No Evidence for Phylostratigraphic Bias Impacting Inferences on Patterns of Gene Emergence and Evolution. Molecular biology and evolution. 2017.", "doi": "10.1093/molbev/msw284", "pmcid": "PMC5400388", "url": "https://pubmed.ncbi.nlm.nih.gov/28087778/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28087778/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28087778", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "computational methods comparator", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Reanalysis argues reported patterns withstand estimated BLAST false-negative rates of 11–15 percent.", "what_it_does_not_show": "Methodological rebuttal is retained; persistence of a trend does not establish an ancestral driver, and cancer-specific proliferation controls are separate.", "confounders_present": [ "Methodological rebuttal is retained; persistence of a trend does not establish an ancestral driver, and cancer-specific proliferation controls are separate." ], "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": "30060201", "title": "Toward Reducing Phylostratigraphic Errors and Biases.", "citation": "Moyers BA, Zhang J et al. Toward Reducing Phylostratigraphic Errors and Biases. Genome biology and evolution. 2018.", "doi": "10.1093/gbe/evy161", "pmcid": "PMC6105108", "url": "https://pubmed.ncbi.nlm.nih.gov/30060201/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30060201/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30060201", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "simulation methods comparator", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Alternative homology tools and error-prediction benchmarks fail to eliminate age-estimation bias; removal can erase or reverse tested trends.", "what_it_does_not_show": "Results concern tested benchmarks, not a definitive refutation of every tumor phylostratigraphic association.", "confounders_present": [ "Results concern tested benchmarks, not a definitive refutation of every tumor phylostratigraphic association." ], "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": "10440377", "title": "Creation of human tumour cells with defined genetic elements.", "citation": "Hahn WC, Counter CM, Lundberg AS et al. Creation of human tumour cells with defined genetic elements. Nature. 1999.", "doi": "10.1038/22780", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10440377/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10440377/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ExpressionOfConcernIn: PMID41986727" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID10440377", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "forced human transformation and xenograft", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Defined hTERT, SV40 early-region and RAS expression historically transformed human cells.", "what_it_does_not_show": "2026 Expression of Concern PMID41986727 concerns possible duplicated Fig1b bands with unavailable raw data; editors retain other support. Kept as examined historical context, excluded from load-bearing positive adjudication.", "confounders_present": [ "2026 Expression of Concern PMID41986727 concerns possible duplicated Fig1b bands with unavailable raw data; editors retain other support. Kept as examined historical context, excluded from load-bearing positive adjudication." ], "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": "11884599", "title": "Enumeration of the simian virus 40 early region elements necessary for human cell transformation.", "citation": "Hahn WC, Dessain SK, Brooks MW et al. Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Molecular and cellular biology. 2002.", "doi": "10.1128/MCB.22.7.2111-2123.2002", "pmcid": "PMC133688", "url": "https://pubmed.ncbi.nlm.nih.gov/11884599/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11884599/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID11884599", "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": "forced human transformation and xenograft", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "SV40 elements disrupting pRB, p53 and PP2A cooperate with telomerase/RAS in human transformation.", "what_it_does_not_show": "Engineered viral/cell-line model and shared Hahn platform; linked erratum has no supplied PMID and unexamined details. Constraint disruption does not distinguish flexible partial atavism by itself.", "confounders_present": [ "Engineered viral/cell-line model and shared Hahn platform; linked erratum has no supplied PMID and unexamined details. Constraint disruption does not distinguish flexible partial atavism by itself." ], "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": "15930270", "title": "Transcriptional programs following genetic alterations in p53, INK4A, and H-Ras genes along defined stages of malignant transformation.", "citation": "Milyavsky M, Tabach Y, Shats I et al. Transcriptional programs following genetic alterations in p53, INK4A, and H-Ras genes along defined stages of malignant transformation. Cancer research. 2005.", "doi": "10.1158/0008-5472.CAN-04-3880", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15930270/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15930270/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID15930270", "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": "forced human fibroblast transformation", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Stepwise p53/INK4A/RAS/hTERT manipulations produce transformation-associated expression shifts.", "what_it_does_not_show": "Installed elements and signatures do not isolate an ancestral network; engineered fibroblasts cannot establish general human initiation.", "confounders_present": [ "Installed elements and signatures do not isolate an ancestral network; engineered fibroblasts cannot establish general human initiation." ], "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": "15604235", "title": "Conditional expression of K-ras in an epithelial compartment that includes the stem cells is sufficient to promote squamous cell carcinogenesis.", "citation": "Vitale-Cross L, Amornphimoltham P, Fisher G et al. Conditional expression of K-ras in an epithelial compartment that includes the stem cells is sufficient to promote squamous cell carcinogenesis. Cancer research. 2004.", "doi": "10.1158/0008-5472.CAN-04-2623", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15604235/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15604235/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID15604235", "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": "conditional epithelial mouse tumors", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Conditional K-RASG12D expression induces tumors in basal epithelium within 10–20 days.", "what_it_does_not_show": "Forced expression proves regulator capability in that tissue, not the absence of all downstream evolutionary reuse.", "confounders_present": [ "Forced expression proves regulator capability in that tissue, not the absence of all downstream evolutionary reuse." ], "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": "21502498", "title": "Modeling high-grade serous ovarian carcinogenesis from the fallopian tube.", "citation": "Karst AM, Levanon K, Drapkin R et al. Modeling high-grade serous ovarian carcinogenesis from the fallopian tube. Proceedings of the National Academy of Sciences of the United States of America. 2011.", "doi": "10.1073/pnas.1017300108", "pmcid": "PMC3088633", "url": "https://pubmed.ncbi.nlm.nih.gov/21502498/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21502498/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID21502498", "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": "forced fallopian epithelial transformation", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Defined elements transform FTSEC, including viral-free p53/CDK4/PP2A changes with hTERT/MYC.", "what_it_does_not_show": "Cultured/xenografted installation is bounded; does not reconstruct or subtract a coherent ancestral program.", "confounders_present": [ "Cultured/xenografted installation is bounded; does not reconstruct or subtract a coherent ancestral program." ], "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": "28138962", "title": "PAX3-FOXO1 is essential for tumour initiation and maintenance but not recurrence in a human myoblast model of rhabdomyosarcoma.", "citation": "Pandey PR, Chatterjee B, Olanich ME et al. PAX3-FOXO1 is essential for tumour initiation and maintenance but not recurrence in a human myoblast model of rhabdomyosarcoma. The Journal of pathology. 2017.", "doi": "10.1002/path.4867", "pmcid": "PMC5357165", "url": "https://pubmed.ncbi.nlm.nih.gov/28138962/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28138962/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28138962", "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 myoblast xenograft regulator withdrawal", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "PAX3-FOXO1/MYCN supports tumor initiation/maintenance; withdrawal regresses tumors but some recur fusion independently.", "what_it_does_not_show": "Immortalized xenograft context; recurrence demonstrates plasticity rather than universal addiction or a universal ancestral route.", "confounders_present": [ "Immortalized xenograft context; recurrence demonstrates plasticity rather than universal addiction or a universal ancestral 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": 16, "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": "2026-10-08", "status_checked_on": "2026-10-08", "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": "Strong", "system": "conditional hematopoietic mouse tumors", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Switching MYC off regresses hematopoietic tumors with apoptosis/differentiation.", "what_it_does_not_show": "Conditional transgene model; MYC necessity here does not logically exclude a required downstream ancestral module.", "confounders_present": [ "Conditional transgene model; MYC necessity here does not logically exclude a required downstream ancestral module." ], "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": "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": "2026-10-08", "status_checked_on": "2026-10-08", "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": "Strong", "system": "conditional osteosarcoma mouse tumors", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Brief MYC inactivation permits sustained differentiation; reactivation induces apoptosis in this model.", "what_it_does_not_show": "Tissue-specific response differs from other MYC systems; no whole ancestral-network test.", "confounders_present": [ "Tissue-specific response differs from other MYC systems; no whole ancestral-network test." ], "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": "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": "2026-10-08", "status_checked_on": "2026-10-08", "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": "Strong", "system": "conditional liver mouse tumors", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "MYC withdrawal produces differentiated dormant tumor-derived liver/biliary cells; reactivation restores tumors.", "what_it_does_not_show": "Dormancy and reactivation differ from irreversible osteosarcoma reversion; conditional model not broad human primacy.", "confounders_present": [ "Dormancy and reactivation differ from irreversible osteosarcoma reversion; conditional model not broad human 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": 19, "pmid": "15613240", "title": "Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis.", "citation": "Pelengaris S, Abouna S, Cheung L et al. Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis. BMC biology. 2004.", "doi": "10.1186/1741-7007-2-26", "pmcid": "PMC544575", "url": "https://pubmed.ncbi.nlm.nih.gov/15613240/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15613240/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID15613240", "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": "conditional islet and skin mouse tumors", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Brief MYC shutdown is insufficient for durable islet/skin reversion, with recurrence influenced by Bcl-xL/context.", "what_it_does_not_show": "A context boundary for regulator dependence, not proof of a single ancient fallback route.", "confounders_present": [ "A context boundary for regulator dependence, not proof of a single ancient fallback 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": 20, "pmid": "15095297", "title": "Reversible lymphomagenesis in conditionally c-MYC expressing mice.", "citation": "Marinkovic D, Marinkovic T, Mahr B et al. Reversible lymphomagenesis in conditionally c-MYC expressing mice. International journal of cancer. 2004.", "doi": "10.1002/ijc.20099", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15095297/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15095297/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID15095297", "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": "conditional lymphoma mouse tumors", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "MYC-transgene withdrawal regresses lymphoma; genomic instability and transgene-related selection accompany recurrence.", "what_it_does_not_show": "Related MYC platforms are not independent biological replications for each paper; selection does not prove program ancestry.", "confounders_present": [ "Related MYC platforms are not independent biological replications for each paper; selection does not prove program ancestry." ], "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": "21969595", "title": "Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction.", "citation": "Choi PS, van Riggelen J, Gentles AJ et al. Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction. Proceedings of the National Academy of Sciences of the United States of America. 2011.", "doi": "10.1073/pnas.1107303108", "pmcid": "PMC3198348", "url": "https://pubmed.ncbi.nlm.nih.gov/21969595/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21969595/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID21969595", "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": "conditional lymphoma and recurrent tumor perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Recurrent tumors restore MYC signaling through tTA mutation/endogenous MYC/Notch, with MYC knockdown dependency.", "what_it_does_not_show": "Restoration through alternative routes supports selected dependency, not universal MYC necessity or ancestral-program independence.", "confounders_present": [ "Restoration through alternative routes supports selected dependency, not universal MYC necessity or ancestral-program independence." ], "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": "22541435", "title": "Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.", "citation": "Ying H, Kimmelman AC, Lyssiotis CA et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012.", "doi": "10.1016/j.cell.2012.01.058", "pmcid": "PMC3472002", "url": "https://pubmed.ncbi.nlm.nih.gov/22541435/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22541435/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID22541435", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "inducible pancreatic mouse tumors", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "KRAS maintains pancreatic tumors and controls anabolic glucose/nonoxidative PPP use.", "what_it_does_not_show": "Conditional oncogene setting; metabolic reprogramming is not a measured evolutionary sequence.", "confounders_present": [ "Conditional oncogene setting; metabolic reprogramming is not a measured evolutionary 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": 23, "pmid": "25119024", "title": "Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function.", "citation": "Viale A, Pettazzoni P, Lyssiotis CA et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature. 2014.", "doi": "10.1038/nature13611", "pmcid": "PMC4376130", "url": "https://pubmed.ncbi.nlm.nih.gov/25119024/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25119024/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID41951747" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25119024", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Main text:paragraph1, 2:Main text:paragraph3, 2:Main text:paragraph6, 2:Main text:paragraph7, 2:Main text:paragraph10, 2:Main text:paragraph16. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "inducible pancreatic tumors and residual-cell pharmacology", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "After KRAS withdrawal, residual cells show respiratory dependence, poor glycolytic compensation and oligomycin-sensitive sphere/regrowth readouts; one of four treated animals remained relapse-free beyond 60 days.", "what_it_does_not_show": "Selected model, pleiotropic drug and small in vivo arm; correction PMID41951747 (2026) lists corrected Fig4a but full notice was unavailable. Not load-bearing alone or fully current figure audit.", "confounders_present": [ "Selected model, pleiotropic drug and small in vivo arm; correction PMID41951747 (2026) lists corrected Fig4a but full notice was unavailable. Not load-bearing alone or fully current figure audit." ], "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": "24954535", "title": "Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.", "citation": "Kapoor A, Yao W, Ying H et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell. 2014.", "doi": "10.1016/j.cell.2014.06.003", "pmcid": "PMC4109295", "url": "https://pubmed.ncbi.nlm.nih.gov/24954535/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24954535/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID31730860" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24954535", "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": "KRAS-independent pancreatic tumor escape", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "YAP1/TEAD2/E2F can bypass KRAS dependence in recurrent pancreatic tumors.", "what_it_does_not_show": "2019 correction PMID31730860 replaces a wrong GFP image in Fig4C; independent quantified graphs reportedly unchanged. Shared inducible platform and corrected image limit independence.", "confounders_present": [ "2019 correction PMID31730860 replaces a wrong GFP image in Fig4C; independent quantified graphs reportedly unchanged. Shared inducible platform and corrected image limit independence." ], "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": "25736685", "title": "Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer.", "citation": "Pettazzoni P, Viale A, Shah P et al. Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer. Cancer research. 2015.", "doi": "10.1158/0008-5472.CAN-14-1854", "pmcid": "PMC4446709", "url": "https://pubmed.ncbi.nlm.nih.gov/25736685/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25736685/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25736685", "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": "conditional pancreatic mouse tumors", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "KRAS ablation kills whereas MEK inhibition is cytostatic; RTK/PI3K compensation motivates combinations.", "what_it_does_not_show": "Genetic removal and incomplete downstream pharmacology differ; effects do not establish ancestor-network necessity.", "confounders_present": [ "Genetic removal and incomplete downstream pharmacology differ; effects do not establish ancestor-network 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": 26, "pmid": "23535601", "title": "Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.", "citation": "Son J, Lyssiotis CA, Ying H et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013.", "doi": "10.1038/nature12040", "pmcid": "PMC3656466", "url": "https://pubmed.ncbi.nlm.nih.gov/23535601/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23535601/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID23535601", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "pancreatic culture and tumor metabolic perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "KRAS-associated GOT1 glutamine/redox pathway supports cultured growth and tumor assays.", "what_it_does_not_show": "Culture/environment and redox pleiotropy; linked erratum details unavailable. Do not treat as universal metabolic dependency.", "confounders_present": [ "Culture/environment and redox pleiotropy; linked erratum details unavailable. Do not treat as universal metabolic 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": 27, "pmid": "35815941", "title": "Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context.", "citation": "Kerk SA, Lin L, Myers AL et al. Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context. eLife. 2022.", "doi": "10.7554/eLife.73245", "pmcid": "PMC9328765", "url": "https://pubmed.ncbi.nlm.nih.gov/35815941/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35815941/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35815941", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "pancreatic culture and endogenous tumor contrast", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "GOT2 loss impairs cultured redox/growth but does not impair tested xenograft/autochthonous tumors; CAF pyruvate rescues culture.", "what_it_does_not_show": "In vivo failure of pyruvate blocking to sensitize shows additional compensation; null is context-specific, not no metabolic causality.", "confounders_present": [ "In vivo failure of pyruvate blocking to sensitize shows additional compensation; null is context-specific, not no metabolic 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": 28, "pmid": "30470748", "title": "Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis.", "citation": "Santana-Codina N, Roeth AA, Zhang Y et al. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nature communications. 2018.", "doi": "10.1038/s41467-018-07472-8", "pmcid": "PMC6251888", "url": "https://pubmed.ncbi.nlm.nih.gov/30470748/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30470748/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30470748", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "pancreatic tumor metabolic perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "KRAS/MAPK/MYC regulates RPIA and nucleotide PPP; intervention affects differential KRAS-sensitive/resistant growth.", "what_it_does_not_show": "Pathway-specific selected dependencies do not imply ordered historical metabolic regression.", "confounders_present": [ "Pathway-specific selected dependencies do not imply ordered historical metabolic regression." ], "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": "26853473", "title": "Metabolic Heterogeneity in Human Lung Tumors.", "citation": "Hensley CT, Faubert B, Yuan Q et al. Metabolic Heterogeneity in Human Lung Tumors. Cell. 2016.", "doi": "10.1016/j.cell.2015.12.034", "pmcid": "PMC4752889", "url": "https://pubmed.ncbi.nlm.nih.gov/26853473/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26853473/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26853473", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph3, 1:RESULTS:paragraph5, 1:RESULTS:paragraph7, 1:RESULTS:paragraph8, 1:RESULTS:paragraph11. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human isotope infusion", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Nine NSCLC patients show glycolytic and TCA labeling with perfusion heterogeneity; NMR positional labeling and relative TCA modeling support glucose oxidation.", "what_it_does_not_show": "Relative labeling/flux fits are not absolute ATP partitioning; circulating lactate and tissue composition confound simple cellular flux inference.", "confounders_present": [ "Relative labeling/flux fits are not absolute ATP partitioning; circulating lactate and tissue composition confound simple cellular flux inference." ], "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": "28985563", "title": "Lactate Metabolism in Human Lung Tumors.", "citation": "Faubert B, Li KY, Cai L et al. Lactate Metabolism in Human Lung Tumors. Cell. 2017.", "doi": "10.1016/j.cell.2017.09.019", "pmcid": "PMC5684706", "url": "https://pubmed.ncbi.nlm.nih.gov/28985563/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28985563/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28985563", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph7, 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph15, 1:Results:paragraph16. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human isotope infusion and transporter xenograft", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Thirty glucose/five lactate-infused lung-cancer patients show lactate oxidation; MCT1 deletion removes lactate labeling in HCC15 xenografts.", "what_it_does_not_show": "Model cannot quantitatively determine net lactate flow; labeled lactate enters other pools. MCT1 knockout preserves culture doubling time: substrate uptake is not demonstrated growth necessity.", "confounders_present": [ "Model cannot quantitatively determine net lactate flow; labeled lactate enters other pools. MCT1 knockout preserves culture doubling time: substrate uptake is not demonstrated growth 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": 31, "pmid": "36044570", "title": "In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.", "citation": "Pachnis P, Wu Z, Faubert B et al. In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors. Science advances. 2022.", "doi": "10.1126/sciadv.abn9550", "pmcid": "PMC9432826", "url": "https://pubmed.ncbi.nlm.nih.gov/36044570/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36044570/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36044570", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "complex-I perturbation and metabolic rescue", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "IACS complex-I inhibition reduces glucose/lactate TCA contributions and increases glutamine; yeast NDI1 NADH-oxidation rescue normalizes relevant labeling.", "what_it_does_not_show": "TCA labeling alone does not measure ETC before perturbation; selective model rescue does not establish a universal tumor respiratory fraction.", "confounders_present": [ "TCA labeling alone does not measure ETC before perturbation; selective model rescue does not establish a universal tumor respiratory fraction." ], "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": "33860280", "title": "Isotope tracing reveals glycolysis and oxidative metabolism in childhood tumors of multiple histologies.", "citation": "Johnston K, Pachnis P, Tasdogan A et al. Isotope tracing reveals glycolysis and oxidative metabolism in childhood tumors of multiple histologies. Med (New York, N.Y.). 2021.", "doi": "10.1016/j.medj.2021.01.002", "pmcid": "PMC8045768", "url": "https://pubmed.ncbi.nlm.nih.gov/33860280/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33860280/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33860280", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human pediatric isotope infusion", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "23 tumors from 22 children show glycolytic/TCA glucose metabolism, with PDH predominant in the studied set.", "what_it_does_not_show": "Restricted diagnoses and intraoperative infusion; labeling does not establish evolutionary ordering or absolute ATP.", "confounders_present": [ "Restricted diagnoses and intraoperative infusion; labeling does not establish evolutionary ordering or absolute ATP." ], "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": "31846640", "title": "Does Tumor FDG-PET Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer?", "citation": "Kernstine KH, Faubert B, Do QN et al. Does Tumor FDG-PET Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer? The Annals of thoracic surgery. 2020.", "doi": "10.1016/j.athoracsur.2019.10.061", "pmcid": "PMC7370816", "url": "https://pubmed.ncbi.nlm.nih.gov/31846640/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31846640/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31846640", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human lung isotope and imaging", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "52 untreated NSCLC tumors show FDG avidity related to proliferation/alternative substrate use rather than a simple glucose-label glycolysis relation.", "what_it_does_not_show": "FDG trapping and isotope enrichment test different processes; no direct whole-program perturbation.", "confounders_present": [ "FDG trapping and isotope enrichment test different processes; no direct whole-program 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": 34, "pmid": "26853747", "title": "Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer.", "citation": "Davidson SM, Papagiannakopoulos T, Olenchock BA et al. Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer. Cell metabolism. 2016.", "doi": "10.1016/j.cmet.2016.01.007", "pmcid": "PMC4785096", "url": "https://pubmed.ncbi.nlm.nih.gov/26853747/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26853747/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26853747", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous lung tumor metabolism", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "RAS-driven lung tumors require pyruvate oxidation in vivo and use less glutamine than cultured counterparts.", "what_it_does_not_show": "Model-specific endogenous dependence and culture mismatch; not a universal lung/metastatic metabolism claim.", "confounders_present": [ "Model-specific endogenous dependence and culture mismatch; not a universal lung/metastatic metabolism claim." ], "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": 35, "pmid": "33811729", "title": "Differential substrate use in EGF- and oncogenic KRAS-stimulated human mammary epithelial cells.", "citation": "Keibler MA, Dong W, Korthauer KD et al. Differential substrate use in EGF- and oncogenic KRAS-stimulated human mammary epithelial cells. The FEBS journal. 2021.", "doi": "10.1111/febs.15858", "pmcid": "PMC8487438", "url": "https://pubmed.ncbi.nlm.nih.gov/33811729/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33811729/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33811729", "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:paragraph10, 1:Results:paragraph11, 1:Results:paragraph12. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "growth-matched human epithelial culture comparator", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "EGF-versus-KRASG12V proliferation matching explains most metabolic shifts in immortalized 184A1 cells; several KRAS-associated fluxes are lower at matched growth.", "what_it_does_not_show": "Growth matching is a useful rival control, not direct validation of all TCGA gene-age associations or intact normal tissue physiology.", "confounders_present": [ "Growth matching is a useful rival control, not direct validation of all TCGA gene-age associations or intact normal tissue physiology." ], "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": "33382985", "title": "Increased demand for NAD+ relative to ATP drives aerobic glycolysis.", "citation": "Luengo A, Li Z, Gui DY et al. Increased demand for NAD+ relative to ATP drives aerobic glycolysis. Molecular cell. 2021.", "doi": "10.1016/j.molcel.2020.12.012", "pmcid": "PMC8315838", "url": "https://pubmed.ncbi.nlm.nih.gov/33382985/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33382985/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33382985", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "metabolic culture perturbation/rescue", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "PDH activation limits growth through NADH accumulation; uncoupling/ATP hydrolysis can restore NAD balance and proliferation.", "what_it_does_not_show": "Aerobic glycolysis can serve redox demands rather than respiratory absence; culture manipulations do not establish whole-tumor universality.", "confounders_present": [ "Aerobic glycolysis can serve redox demands rather than respiratory absence; culture manipulations do not establish whole-tumor universality." ], "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": "34223403", "title": "Local production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer.", "citation": "Ghergurovich JM, Lang JD, Levin MK et al. Local production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer. Med (New York, N.Y.). 2021.", "doi": "10.1016/j.medj.2021.03.009", "pmcid": "PMC8248508", "url": "https://pubmed.ncbi.nlm.nih.gov/34223403/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34223403/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34223403", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human triple-negative breast isotope infusion", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Tumors show glycolysis, oxidative PPP-derived ribose and TCA amino-acid contributions, with lactate exchange differing from lung tumors.", "what_it_does_not_show": "Tumor-type heterogeneity rather than a longitudinal evolutionary series; labels are not absolute ATP fractions.", "confounders_present": [ "Tumor-type heterogeneity rather than a longitudinal evolutionary series; labels are not absolute ATP fractions." ], "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": 38, "pmid": "24279929", "title": "The metabolic demands of cancer cells are coupled to their size and protein synthesis rates.", "citation": "Dolfi SC, Chan LL, Qiu J et al. The metabolic demands of cancer cells are coupled to their size and protein synthesis rates. Cancer & metabolism. 2013.", "doi": "10.1186/2049-3002-1-20", "pmcid": "PMC4178206", "url": "https://pubmed.ncbi.nlm.nih.gov/24279929/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24279929/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24279929", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "NCI60 metabolic growth comparator", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Flux, protein synthesis and cell-size comparisons relate metabolism to proliferation across NCI60.", "what_it_does_not_show": "Cell-line panel/compositional scaling cannot separate all tissue/genotype effects or infer an ancestral network.", "confounders_present": [ "Cell-line panel/compositional scaling cannot separate all tissue/genotype effects or infer an ancestral network." ], "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": "19693011", "title": "Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment.", "citation": "Schafer ZT, Grassian AR, Song L et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature. 2009.", "doi": "10.1038/nature08268", "pmcid": "PMC2931797", "url": "https://pubmed.ncbi.nlm.nih.gov/19693011/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19693011/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID19693011", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human mammary matrix-detachment culture", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "ERBB2/EGFR/PI3K restores detached-cell glucose/PPP support; antioxidant rescue enables fatty-acid oxidation without restoring glucose uptake.", "what_it_does_not_show": "Context/pleiotropy and culture assays; survival rescue is not coherent ancient-program reconstitution.", "confounders_present": [ "Context/pleiotropy and culture assays; survival rescue is not coherent ancient-program reconstitution." ], "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": "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": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID9105051", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph7. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "3D breast culture and xenograft pretreatment", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Function-blocking beta1-integrin antibodies/Fab revert malignant 3D phenotypes; washout restores malignancy, and brief pretreatment lowers xenograft nodules.", "what_it_does_not_show": "Reversible single-line tissue signaling context; not universal genotype independence or reversion of all malignancy.", "confounders_present": [ "Reversible single-line tissue signaling context; not universal genotype independence or reversion of all malignancy." ], "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": "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": "2026-10-08", "status_checked_on": "2026-10-08", "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": "3D human breast mechanical perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Brief compression yields more normal acini with NO-dependent response.", "what_it_does_not_show": "Physical context and selected 3D readouts, not endogenous in vivo cancer eradication or ancestry-specific perturbation.", "confounders_present": [ "Physical context and selected 3D readouts, not endogenous in vivo cancer eradication or ancestry-specific 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": 42, "pmid": "17456778", "title": "Epigenetic reversion of breast carcinoma phenotype is accompanied by changes in DNA sequestration as measured by AluI restriction enzyme.", "citation": "Sandal T, Valyi-Nagy K, Spencer VA et al. Epigenetic reversion of breast carcinoma phenotype is accompanied by changes in DNA sequestration as measured by AluI restriction enzyme. The American journal of pathology. 2007.", "doi": "10.2353/ajpath.2007.060922", "pmcid": "PMC1854967", "url": "https://pubmed.ncbi.nlm.nih.gov/17456778/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17456778/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID17456778", "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": "3D breast culture reversion", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "cAMP/PI3K/fibronectin interventions alter malignant organization and chromatin accessibility.", "what_it_does_not_show": "Related HMT model platform; pleiotropic reversion does not establish restoration of an intact ancestral or metazoan network.", "confounders_present": [ "Related HMT model platform; pleiotropic reversion does not establish restoration of an intact ancestral or metazoan network." ], "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": "25057922", "title": "Network analysis of breast cancer progression and reversal using a tree-evolving network algorithm.", "citation": "Parikh AP, Curtis RE, Kuhn I et al. Network analysis of breast cancer progression and reversal using a tree-evolving network algorithm. PLoS computational biology. 2014.", "doi": "10.1371/journal.pcbi.1003713", "pmcid": "PMC4109850", "url": "https://pubmed.ncbi.nlm.nih.gov/25057922/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25057922/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25057922", "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": "Weak", "system": "computational 3D breast reversion networks", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Tree-based network reconstruction identifies differing routes and compensations in reverted HMT phenotypes.", "what_it_does_not_show": "Same series/model as prior 3D studies, with inferred edges rather than independent endogenous causal replication.", "confounders_present": [ "Same series/model as prior 3D studies, with inferred edges rather than independent endogenous causal replication." ], "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": "20103652", "title": "SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation.", "citation": "Thomsen MK, Ambroisine L, Wynn S et al. SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation. Cancer research. 2010.", "doi": "10.1158/0008-5472.CAN-09-2370", "pmcid": "PMC3083842", "url": "https://pubmed.ncbi.nlm.nih.gov/20103652/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20103652/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID20103652", "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": "endogenous prostate mouse perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "SOX9 boosts proliferation without hyperplasia alone, enhances Pten-associated PIN and is attenuated by knockout.", "what_it_does_not_show": "A metazoan developmental pathway can contribute without sufficiency; context-specific genetic interaction.", "confounders_present": [ "A metazoan developmental pathway can contribute without sufficiency; context-specific genetic interaction." ], "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": "16204040", "title": "Overlapping gene expression in fetal mouse intestine development and human colorectal cancer.", "citation": "Hu M, Shivdasani RA et al. Overlapping gene expression in fetal mouse intestine development and human colorectal cancer. Cancer research. 2005.", "doi": "10.1158/0008-5472.CAN-05-0700", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16204040/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16204040/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID16204040", "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" ], "favors_models": [], "evidence_class": "Weak", "system": "human fetal/tumor expression", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Colon cancers share 8–19 percent of fetal intestinal signatures compared with 1–6 percent in other tissues.", "what_it_does_not_show": "Developmental lineage similarity is not pre-metazoan program identity or causal dependency.", "confounders_present": [ "Developmental lineage similarity is not pre-metazoan program identity or causal 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": 46, "pmid": "18794802", "title": "Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer.", "citation": "Schaeffer EM, Marchionni L, Huang Z et al. Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer. Oncogene. 2008.", "doi": "10.1038/onc.2008.327", "pmcid": "PMC2676849", "url": "https://pubmed.ncbi.nlm.nih.gov/18794802/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18794802/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID18794802", "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" ], "favors_models": [], "evidence_class": "Weak", "system": "embryonic prostate and human tumor expression", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Androgen-induced embryonic prostate programs are enriched in lethal prostate tumors.", "what_it_does_not_show": "Metazoan lineage-program overlap and association; no selective driver subtraction/rescue.", "confounders_present": [ "Metazoan lineage-program overlap and association; no selective driver subtraction/rescue." ], "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": "35354817", "title": "Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma.", "citation": "Prummel KD, Crowell HL, Nieuwenhuize S et al. Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma. Nature communications. 2022.", "doi": "10.1038/s41467-022-29311-7", "pmcid": "PMC8967825", "url": "https://pubmed.ncbi.nlm.nih.gov/35354817/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35354817/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35354817", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "zebrafish/mouse development and human mesothelioma", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Hand2 loss affects mesothelial development; reactivation is observed in mesothelioma.", "what_it_does_not_show": "Developmental loss-of-function is not tumor Hand2 necessity, and reactivation is of a later multicellular program.", "confounders_present": [ "Developmental loss-of-function is not tumor Hand2 necessity, and reactivation is of a later multicellular program." ], "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": "31492871", "title": "SOX11 and SOX4 drive the reactivation of an embryonic gene program during murine wound repair.", "citation": "Miao Q, Hill MC, Chen F et al. SOX11 and SOX4 drive the reactivation of an embryonic gene program during murine wound repair. Nature communications. 2019.", "doi": "10.1038/s41467-019-11880-9", "pmcid": "PMC6731344", "url": "https://pubmed.ncbi.nlm.nih.gov/31492871/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31492871/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31492871", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "nonmalignant mouse wound-repair comparator", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "SOX11/4 embryonic-state induction and knockout influence normal repair through targets including fascin.", "what_it_does_not_show": "Physiological embryonic reuse can occur without cancer; normal repair comparator is not tumor-program disproof.", "confounders_present": [ "Physiological embryonic reuse can occur without cancer; normal repair comparator is not tumor-program disproof." ], "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": "22397650", "title": "Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.", "citation": "Gerlinger M, Rowan AJ, Horswell S et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England journal of medicine. 2012.", "doi": "10.1056/NEJMoa1113205", "pmcid": "PMC4878653", "url": "https://pubmed.ncbi.nlm.nih.gov/22397650/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22397650/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID22397650", "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 multiregion renal phylogeny", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Four renal tumors show branched regional evolution with 63–69 percent of somatic alterations not shared across regions.", "what_it_does_not_show": "Heterogeneity does not exclude a conserved underlying program; linked erratum details unavailable and no ancestral-state perturbation.", "confounders_present": [ "Heterogeneity does not exclude a conserved underlying program; linked erratum details unavailable and no ancestral-state 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": 50, "pmid": "37046096", "title": "The evolution of lung cancer and impact of subclonal selection in TRACERx.", "citation": "Frankell AM, Dietzen M, Al Bakir M et al. The evolution of lung cancer and impact of subclonal selection in TRACERx. Nature. 2023.", "doi": "10.1038/s41586-023-05783-5", "pmcid": "PMC10115649", "url": "https://pubmed.ncbi.nlm.nih.gov/37046096/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37046096/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID38965439" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID37046096", "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 longitudinal lung clonal analysis", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "TRACERx 1644 regions from 421 patients documents branching, whole-genome duplication and subclonal selection associated with relapse.", "what_it_does_not_show": "2024 correction swaps death/censor symbols in Fig1; original notice examined. Clonal selection is not itself proof against all ancient cellular modules.", "confounders_present": [ "2024 correction swaps death/censor symbols in Fig1; original notice examined. Clonal selection is not itself proof against all ancient cellular modules." ], "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": 51, "pmid": "25979483", "title": "Subclonal Genomic Architectures of Primary and Metastatic Colorectal Cancer Based on Intratumoral Genetic Heterogeneity.", "citation": "Kim TM, Jung SH, An CH et al. Subclonal Genomic Architectures of Primary and Metastatic Colorectal Cancer Based on Intratumoral Genetic Heterogeneity. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015.", "doi": "10.1158/1078-0432.CCR-14-2413", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25979483/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25979483/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25979483", "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 colorectal metastatic phylogeny", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Five primary/liver-metastasis cases show branched genetic heterogeneity.", "what_it_does_not_show": "Small observational phylogeny cannot identify a specific regulatory mechanism or exclude a shared function.", "confounders_present": [ "Small observational phylogeny cannot identify a specific regulatory mechanism or exclude a shared function." ], "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": "36476508", "title": "Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors.", "citation": "Kang M, Na HY, Ahn S et al. Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors. eLife. 2022.", "doi": "10.7554/eLife.78636", "pmcid": "PMC9771369", "url": "https://pubmed.ncbi.nlm.nih.gov/36476508/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36476508/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36476508", "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 gallbladder precursor/metastasis phylogeny", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Eleven cases show early branching among precursor, primary and metastatic lesions.", "what_it_does_not_show": "Timing/branching inference is not direct ancestor-program activity or causal removal.", "confounders_present": [ "Timing/branching inference is not direct ancestor-program activity or causal removal." ], "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": "37042990", "title": "The clonal heterogeneity of colon cancer with liver metastases.", "citation": "Chen G, Zhu W, Liu Y et al. The clonal heterogeneity of colon cancer with liver metastases. Journal of gastroenterology. 2023.", "doi": "10.1007/s00535-023-01989-6", "pmcid": "PMC10307713", "url": "https://pubmed.ncbi.nlm.nih.gov/37042990/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37042990/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID37042990", "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 colorectal multisite phylogeny", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Thirty samples from eight patients exhibit parallel, linear and branched routes.", "what_it_does_not_show": "Multiple routes constrain a rigid trajectory but are not direct tests of all atavism variants.", "confounders_present": [ "Multiple routes constrain a rigid trajectory but are not direct tests of all atavism variants." ], "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": "31853067", "title": "Metabolic heterogeneity confers differences in melanoma metastatic potential.", "citation": "Tasdogan A, Faubert B, Ramesh V et al. Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature. 2020.", "doi": "10.1038/s41586-019-1847-2", "pmcid": "PMC6930341", "url": "https://pubmed.ncbi.nlm.nih.gov/31853067/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31853067/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31853067", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "melanoma patient-derived xenograft perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "MCT1 perturbation reduces metastasis without equivalent primary-growth effects; antioxidants rescue selected readouts.", "what_it_does_not_show": "Relapse/metastatic metabolism differs from primary growth and culture uptake; transplantation context limits generality.", "confounders_present": [ "Relapse/metastatic metabolism differs from primary growth and culture uptake; transplantation context limits generality." ], "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": "25007966", "title": "Metabolic differences in breast cancer stem cells and differentiated progeny.", "citation": "Vlashi E, Lagadec C, Vergnes L et al. Metabolic differences in breast cancer stem cells and differentiated progeny. Breast cancer research and treatment. 2014.", "doi": "10.1007/s10549-014-3051-2", "pmcid": "PMC4131557", "url": "https://pubmed.ncbi.nlm.nih.gov/25007966/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25007966/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25007966", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human breast stem/differentiated culture", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Stem-like cells show greater oxidative capacity and less lactate than differentiated counterparts; irradiation alters states.", "what_it_does_not_show": "Marker/culture selection does not establish a stable endogenous hierarchy or ordered backward evolution.", "confounders_present": [ "Marker/culture selection does not establish a stable endogenous hierarchy or ordered backward 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": 56, "pmid": "10683245", "title": "Substrate oxidation and ATP supply in AS-30D hepatoma cells.", "citation": "Rodríguez-Enríquez S, Torres-Márquez ME, Moreno-Sánchez R et al. Substrate oxidation and ATP supply in AS-30D hepatoma cells. Archives of biochemistry and biophysics. 2000.", "doi": "10.1006/abbi.1999.1582", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10683245/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10683245/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID10683245", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "hepatoma culture metabolism", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "AS30D hepatoma respiration/oligomycin analyses estimate predominantly oxidative ATP production.", "what_it_does_not_show": "Single cell model and ATP estimation assumptions; does not quantify all human cancers.", "confounders_present": [ "Single cell model and ATP estimation assumptions; does not quantify all human 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": 57, "pmid": "32153327", "title": "The Quiescent Metabolic Phenotype of Glioma Stem Cells.", "citation": "Spehalski EI, Lee JA, Peters C et al. The Quiescent Metabolic Phenotype of Glioma Stem Cells. Journal of proteomics & bioinformatics. 2019.", "doi": "10.35248/0974-276x.19.12.502", "pmcid": "PMC7061459", "url": "https://pubmed.ncbi.nlm.nih.gov/32153327/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32153327/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32153327", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "glioma stem-like culture", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Quiescent glioma stem-like populations have low glycolytic and oxidative rates with metabolic heterogeneity after irradiation.", "what_it_does_not_show": "Cultured selection and state-specific output, not generalized tumor-wide respiratory failure or a serial evolutionary order.", "confounders_present": [ "Cultured selection and state-specific output, not generalized tumor-wide respiratory failure or a serial evolutionary 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": 58, "pmid": "32315286", "title": "HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models.", "citation": "Nguyen TTT, Zhang Y, Shang E et al. HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models. The Journal of clinical investigation. 2020.", "doi": "10.1172/JCI129049", "pmcid": "PMC7324177", "url": "https://pubmed.ncbi.nlm.nih.gov/32315286/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32315286/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32315286", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "glioma culture and patient-derived tumors", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "HDAC inhibition lowers MYC and raises PGC1/PPAR-linked FAO/OXPHOS; combined FAO/HDAC intervention improves tested tumor-model survival.", "what_it_does_not_show": "Drug pleiotropy and selected settings; induced forward adaptation fits metabolic plasticity without ancestry-specific identification.", "confounders_present": [ "Drug pleiotropy and selected settings; induced forward adaptation fits metabolic plasticity without ancestry-specific identification." ], "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": "28835371", "title": "B-cell Receptor Signaling Regulates Metabolism in Chronic Lymphocytic Leukemia.", "citation": "Vangapandu HV, Havranek O, Ayres ML et al. B-cell Receptor Signaling Regulates Metabolism in Chronic Lymphocytic Leukemia. Molecular cancer research : MCR. 2017.", "doi": "10.1158/1541-7786.MCR-17-0026", "pmcid": "PMC5714317", "url": "https://pubmed.ncbi.nlm.nih.gov/28835371/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28835371/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28835371", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human CLL ex vivo perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "45-patient CLL cohort shows variable respiration linked to prognosis; BCR/PI3K perturbation reduces OCR and ECAR.", "what_it_does_not_show": "Ex vivo signaling and association do not establish universal respiratory dependency or evolutionary ordering.", "confounders_present": [ "Ex vivo signaling and association do not establish universal respiratory dependency or evolutionary ordering." ], "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": 64, "verified": 64, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Β", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Association-only cancer claims cap at Β.", "specific_trigger": "Β: ancient-expression and coexpression patterns are human associations, with a real methods debate and incomplete matched-normal proliferation controls.", "resulting_ceiling": "Β" }, { "subclaim_id": "SC2", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Mechanistically plausible cell culture or transplantation-linked models without endogenous in vivo dependency cap at Γ.", "specific_trigger": "Γ: network/mutation/dependency integration supplies mechanistic plausibility and culture perturbations, but not recovery, selective subtraction or rescue of a predeclared coherent ancestral program. New mixed modules favor rewiring.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC3", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Mechanistically plausible cell culture or transplantation-linked models without endogenous in vivo dependency cap at Γ.", "specific_trigger": "Γ: functional regulator and metabolic dependencies exist, but no program-specific endogenous in vivo initiation/maintenance/relapse dependence establishes the nominal driver.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC4", "cap": "Β", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Association-only cancer claims cap at Β.", "specific_trigger": "Β: metabolic state associations are heterogeneous; retained oxidation and treatment-selected respiratory states constrain serial regression, and no registered longitudinal evolutionary order was tested.", "resulting_ceiling": "Β" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Cancer is the re-expression of a coherent, pre-existing ancestral pre-metazoan gene-regulatory program, and that program drives tumorigenesis.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "The 02 cancer rubric governs the driver and generalization burdens; 03 secondary guidance cautions that chromatin/expression states are not regulatory causation. True MYC/KRAS genetic dependencies and individual CRISPR phenotypes are retained at their own scope. Their convergence does not identify the ancestry-specific network required by SC2/SC3, so the assembled set still lacks the distinctive experiment.", "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": "no", "qualifying_evidence_citation": "PMID30803482, PMID25312911, PMID28637261, PMID28087778, PMID30060201, PMID33811729, PMID31492871", "gamma_hard_rules_triggered": [ "Bulk network ages, coexpression and individual CRISPR dependencies do not establish an executed whole ancestral program.", "In vitro or transplant specificity and forced regulator dependence cannot be transferred to coherent-program primacy in endogenous cancer." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Β: ancient-expression and coexpression patterns are human associations, with a real methods debate and incomplete matched-normal proliferation controls.", "ceiling_from_boundary_check": "Γ" }, { "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": "no", "qualifying_evidence_citation": "PMID30803482, PMID11884599, PMID15930270, PMID15604235, PMID21502498, PMID28138962, PMID10488335, PMID12098700, PMID15475948, PMID15613240, PMID15095297, PMID21969595, PMID22541435, PMID24954535, PMID25736685, PMID9105051, PMID29560858, PMID17456778, PMID20103652, PMID35354817, PMID31492871", "gamma_hard_rules_triggered": [ "Bulk network ages, coexpression and individual CRISPR dependencies do not establish an executed whole ancestral program.", "In vitro or transplant specificity and forced regulator dependence cannot be transferred to coherent-program primacy in endogenous cancer." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Γ: network/mutation/dependency integration supplies mechanistic plausibility and culture perturbations, but not recovery, selective subtraction or rescue of a predeclared coherent ancestral program. New mixed modules favor rewiring.", "ceiling_from_boundary_check": "Γ" }, { "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": "no", "qualifying_evidence_citation": "PMID30803482, PMID11884599, PMID15930270, PMID15604235, PMID21502498, PMID28138962, PMID10488335, PMID12098700, PMID15475948, PMID15613240, PMID15095297, PMID21969595, PMID22541435, PMID25119024, PMID24954535, PMID25736685, PMID23535601, PMID35815941, PMID30470748, PMID26853747, PMID19693011, PMID9105051, PMID29560858, PMID17456778, PMID20103652, PMID31853067, PMID32315286, PMID28835371", "gamma_hard_rules_triggered": [ "Bulk network ages, coexpression and individual CRISPR dependencies do not establish an executed whole ancestral program.", "In vitro or transplant specificity and forced regulator dependence cannot be transferred to coherent-program primacy in endogenous cancer." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Γ: functional regulator and metabolic dependencies exist, but no program-specific endogenous in vivo initiation/maintenance/relapse dependence establishes the nominal driver.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "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": "no", "qualifying_evidence_citation": "PMID22541435, PMID25119024, PMID23535601, PMID35815941, PMID30470748, PMID28985563, PMID36044570, PMID26853747, PMID33811729, PMID33382985, PMID19693011, PMID31853067, PMID25007966, PMID10683245, PMID32153327, PMID32315286, PMID28835371", "gamma_hard_rules_triggered": [ "Bulk network ages, coexpression and individual CRISPR dependencies do not establish an executed whole ancestral program.", "In vitro or transplant specificity and forced regulator dependence cannot be transferred to coherent-program primacy in endogenous cancer." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Β: metabolic state associations are heterogeneous; retained oxidation and treatment-selected respiratory states constrain serial regression, and no registered longitudinal evolutionary order was tested.", "ceiling_from_boundary_check": "Γ" } ], "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": "no", "supporting_evidence": [ "[2] Thirty solid cancer types connect mutation/CNA strata to UC-MC regulatory links; 364 Avana cell-line CRISPR screens and 250-drug data inform dependency/response associations.", "[6] Simulations show homology-detection error can bias inferred gene ages and expression-age trends.", "[7] Further simulations and empirical-method assessment identify systematic phylostratigraphic errors.", "[8] Reanalysis argues reported patterns withstand estimated BLAST false-negative rates of 11–15 percent.", "[9] Alternative homology tools and error-prediction benchmarks fail to eliminate age-estimation bias; removal can erase or reverse tested trends.", "[35] EGF-versus-KRASG12V proliferation matching explains most metabolic shifts in immortalized 184A1 cells; several KRAS-associated fluxes are lower at matched growth.", "[48] SOX11/4 embryonic-state induction and knockout influence normal repair through targets including fascin." ], "what_would_cross_it": "A prespecified causal test matching this subclaim, with mechanistic engagement, meaningful phenotype change and an appropriate negative control." }, { "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": "no", "supporting_evidence": [ "[2] Thirty solid cancer types connect mutation/CNA strata to UC-MC regulatory links; 364 Avana cell-line CRISPR screens and 250-drug data inform dependency/response associations.", "[11] SV40 elements disrupting pRB, p53 and PP2A cooperate with telomerase/RAS in human transformation.", "[12] Stepwise p53/INK4A/RAS/hTERT manipulations produce transformation-associated expression shifts.", "[13] Conditional K-RASG12D expression induces tumors in basal epithelium within 10–20 days.", "[14] Defined elements transform FTSEC, including viral-free p53/CDK4/PP2A changes with hTERT/MYC.", "[15] PAX3-FOXO1/MYCN supports tumor initiation/maintenance; withdrawal regresses tumors but some recur fusion independently.", "[16] Switching MYC off regresses hematopoietic tumors with apoptosis/differentiation.", "[17] Brief MYC inactivation permits sustained differentiation; reactivation induces apoptosis in this model.", "[18] MYC withdrawal produces differentiated dormant tumor-derived liver/biliary cells; reactivation restores tumors.", "[19] Brief MYC shutdown is insufficient for durable islet/skin reversion, with recurrence influenced by Bcl-xL/context.", "[20] MYC-transgene withdrawal regresses lymphoma; genomic instability and transgene-related selection accompany recurrence.", "[21] Recurrent tumors restore MYC signaling through tTA mutation/endogenous MYC/Notch, with MYC knockdown dependency.", "[22] KRAS maintains pancreatic tumors and controls anabolic glucose/nonoxidative PPP use.", "[24] YAP1/TEAD2/E2F can bypass KRAS dependence in recurrent pancreatic tumors.", "[25] KRAS ablation kills whereas MEK inhibition is cytostatic; RTK/PI3K compensation motivates combinations.", "[40] Function-blocking beta1-integrin antibodies/Fab revert malignant 3D phenotypes; washout restores malignancy, and brief pretreatment lowers xenograft nodules.", "[41] Brief compression yields more normal acini with NO-dependent response.", "[42] cAMP/PI3K/fibronectin interventions alter malignant organization and chromatin accessibility.", "[44] SOX9 boosts proliferation without hyperplasia alone, enhances Pten-associated PIN and is attenuated by knockout.", "[47] Hand2 loss affects mesothelial development; reactivation is observed in mesothelioma.", "[48] SOX11/4 embryonic-state induction and knockout influence normal repair through targets including fascin." ], "what_would_cross_it": "A prespecified causal test matching this subclaim, with mechanistic engagement, meaningful phenotype change and an appropriate negative control." }, { "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": "no", "supporting_evidence": [ "[2] Thirty solid cancer types connect mutation/CNA strata to UC-MC regulatory links; 364 Avana cell-line CRISPR screens and 250-drug data inform dependency/response associations.", "[11] SV40 elements disrupting pRB, p53 and PP2A cooperate with telomerase/RAS in human transformation.", "[12] Stepwise p53/INK4A/RAS/hTERT manipulations produce transformation-associated expression shifts.", "[13] Conditional K-RASG12D expression induces tumors in basal epithelium within 10–20 days.", "[14] Defined elements transform FTSEC, including viral-free p53/CDK4/PP2A changes with hTERT/MYC.", "[15] PAX3-FOXO1/MYCN supports tumor initiation/maintenance; withdrawal regresses tumors but some recur fusion independently.", "[16] Switching MYC off regresses hematopoietic tumors with apoptosis/differentiation.", "[17] Brief MYC inactivation permits sustained differentiation; reactivation induces apoptosis in this model.", "[18] MYC withdrawal produces differentiated dormant tumor-derived liver/biliary cells; reactivation restores tumors.", "[19] Brief MYC shutdown is insufficient for durable islet/skin reversion, with recurrence influenced by Bcl-xL/context.", "[20] MYC-transgene withdrawal regresses lymphoma; genomic instability and transgene-related selection accompany recurrence.", "[21] Recurrent tumors restore MYC signaling through tTA mutation/endogenous MYC/Notch, with MYC knockdown dependency.", "[22] KRAS maintains pancreatic tumors and controls anabolic glucose/nonoxidative PPP use.", "[23] After KRAS withdrawal, residual cells show respiratory dependence, poor glycolytic compensation and oligomycin-sensitive sphere/regrowth readouts; one of four treated animals remained relapse-free beyond 60 days.", "[24] YAP1/TEAD2/E2F can bypass KRAS dependence in recurrent pancreatic tumors.", "[25] KRAS ablation kills whereas MEK inhibition is cytostatic; RTK/PI3K compensation motivates combinations.", "[26] KRAS-associated GOT1 glutamine/redox pathway supports cultured growth and tumor assays.", "[27] GOT2 loss impairs cultured redox/growth but does not impair tested xenograft/autochthonous tumors; CAF pyruvate rescues culture.", "[28] KRAS/MAPK/MYC regulates RPIA and nucleotide PPP; intervention affects differential KRAS-sensitive/resistant growth.", "[34] RAS-driven lung tumors require pyruvate oxidation in vivo and use less glutamine than cultured counterparts.", "[39] ERBB2/EGFR/PI3K restores detached-cell glucose/PPP support; antioxidant rescue enables fatty-acid oxidation without restoring glucose uptake.", "[40] Function-blocking beta1-integrin antibodies/Fab revert malignant 3D phenotypes; washout restores malignancy, and brief pretreatment lowers xenograft nodules.", "[41] Brief compression yields more normal acini with NO-dependent response.", "[42] cAMP/PI3K/fibronectin interventions alter malignant organization and chromatin accessibility.", "[44] SOX9 boosts proliferation without hyperplasia alone, enhances Pten-associated PIN and is attenuated by knockout.", "[54] MCT1 perturbation reduces metastasis without equivalent primary-growth effects; antioxidants rescue selected readouts.", "[58] HDAC inhibition lowers MYC and raises PGC1/PPAR-linked FAO/OXPHOS; combined FAO/HDAC intervention improves tested tumor-model survival.", "[59] 45-patient CLL cohort shows variable respiration linked to prognosis; BCR/PI3K perturbation reduces OCR and ECAR." ], "what_would_cross_it": "A prespecified causal test matching this subclaim, with mechanistic engagement, meaningful phenotype change and an appropriate negative control." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "no", "supporting_evidence": [ "[22] KRAS maintains pancreatic tumors and controls anabolic glucose/nonoxidative PPP use.", "[23] After KRAS withdrawal, residual cells show respiratory dependence, poor glycolytic compensation and oligomycin-sensitive sphere/regrowth readouts; one of four treated animals remained relapse-free beyond 60 days.", "[26] KRAS-associated GOT1 glutamine/redox pathway supports cultured growth and tumor assays.", "[27] GOT2 loss impairs cultured redox/growth but does not impair tested xenograft/autochthonous tumors; CAF pyruvate rescues culture.", "[28] KRAS/MAPK/MYC regulates RPIA and nucleotide PPP; intervention affects differential KRAS-sensitive/resistant growth.", "[30] Thirty glucose/five lactate-infused lung-cancer patients show lactate oxidation; MCT1 deletion removes lactate labeling in HCC15 xenografts.", "[31] IACS complex-I inhibition reduces glucose/lactate TCA contributions and increases glutamine; yeast NDI1 NADH-oxidation rescue normalizes relevant labeling.", "[34] RAS-driven lung tumors require pyruvate oxidation in vivo and use less glutamine than cultured counterparts.", "[35] EGF-versus-KRASG12V proliferation matching explains most metabolic shifts in immortalized 184A1 cells; several KRAS-associated fluxes are lower at matched growth.", "[36] PDH activation limits growth through NADH accumulation; uncoupling/ATP hydrolysis can restore NAD balance and proliferation.", "[39] ERBB2/EGFR/PI3K restores detached-cell glucose/PPP support; antioxidant rescue enables fatty-acid oxidation without restoring glucose uptake.", "[54] MCT1 perturbation reduces metastasis without equivalent primary-growth effects; antioxidants rescue selected readouts.", "[55] Stem-like cells show greater oxidative capacity and less lactate than differentiated counterparts; irradiation alters states.", "[56] AS30D hepatoma respiration/oligomycin analyses estimate predominantly oxidative ATP production.", "[57] Quiescent glioma stem-like populations have low glycolytic and oxidative rates with metabolic heterogeneity after irradiation.", "[58] HDAC inhibition lowers MYC and raises PGC1/PPAR-linked FAO/OXPHOS; combined FAO/HDAC intervention improves tested tumor-model survival.", "[59] 45-patient CLL cohort shows variable respiration linked to prognosis; BCR/PI3K perturbation reduces OCR and ECAR." ], "what_would_cross_it": "A prespecified causal test matching this subclaim, with mechanistic engagement, meaningful phenotype change and an appropriate negative control." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Matched TCGA normal tissue, normal coexpression and 16 normal cohorts in the 2024 novelty comparison.", "Gene-age error simulations and methodological rebuttal assessed together.", "EGF/KRAS growth matching with predefined effect-size thresholds.", "MYC off/on tissue contrasts, integrin nonfunctional/activating antibodies and reversible washout cycles.", "In vivo/culture GOT2 contrast and labeled-substrate/MCT1 controls." ], "note": "Cancer lineage, cell proliferation, tumor/normal composition, conditional versus endogenous disease, primary versus residual/metastatic state and cultured versus physiologic metabolism are explicitly contrasted. Coherent ancestry is not redefined to whichever state survived intervention." }, "falsification_patterns_met": [ { "pattern": "Proposed metabolic dependency disappears in physiologic tumor context", "evidence": "GOT2 loss impairs culture but not tested in vivo tumors, PMID35815941.", "downgrade_applied": false }, { "pattern": "Rigid metabolic regression conflicts with retained/adaptive oxidation", "evidence": "Human isotope and residual-cell results PMID26853473,28985563,25119024.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Gene ancestry equated with regulatory-program ancestry", "where": "Protein conservation and coexpression do not reconstruct ancestral regulatory edges." }, { "pitfall": "No program rescue misreported as no perturbation evidence", "where": "Trigos 2019 incorporates genuine single-gene CRISPR screens." }, { "pitfall": "Inferred grade order equated with prospective tumor history", "where": "Cross-sectional TCGA classes do not trace an individual LGG-to-GBM trajectory." }, { "pitfall": "Isotope labels equated with absolute ATP/ETC flux", "where": "Relative enrichment, recirculation and model identifiability retained." }, { "pitfall": "Source integrity notices silently ignored", "where": "1999 EOC and 2014/2019/2024 corrections separately reconciled." } ], "causal_tally_audit": { "tally_claimed_by_document": 41, "tally_after_audit": 41, "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": "Steelman Δ: UC-MC hubs have mutations, dependency screens and drug-response associations; disabling oncogenes or metabolism changes cancer phenotype. The missing discriminator is whether a coherent ancestral program, rather than these individual indispensable processes, was selectively perturbed.", "case_one_rung_lower": "Steelman Β: no intact ancestral network has been measured or rescued, and main human evidence is associative. Γ is retained because integrated dependency data and specific mechanistic culture/model evidence add plausible links, while the paired gate and weaker association sensitivities are explicit.", "which_rejected": "Retain Γ with Moderate confidence; do not promote generic conserved-gene necessity to ancestral-program causality. Weakest-link Β is disclosed, not suppressed.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Preregister an orthology-robust ancestral edge-defined network, then selectively sever its proposed conserved regulatory edges in autochthonous lineage-matched tumors and growth-matched normal tissues, rescue with edge-specific restoration, and track initiation, maintenance and relapse separately." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Evidence density and reproducibility set the band: 59 primary reports, but the distinctive coherent-program claim rests on a small set of analyses sharing TCGA data and gene-age assignments with no independent biological replication, and the metabolic literature is openly heterogeneous. Access depth is reported separately and is not a determinant of confidence (rationale corrected 2026-10-14 in adversarial review; band unchanged).", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered primary SC3 returns Γ. The mandatory paired SC2/SC3 minimum also returns Γ; weakest-link returns Β because SC1/SC4 remain associative, and scope-matched primacy returns Γ. The score concerns the distinctive coherent-program driver, not the proven existence of ancient genes or selected oncogene dependencies." }, "role_of_mechanism": { "classification": "epiphenomenon", "derivation_step_matched": 2, "derivation": "Step 2: no directional causal dependency is demonstrated for the nominal coherent ancestral program. This records unestablished program causation, not biological inertness of conserved genes; specific regulators and metabolic pathways can be causal.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "2024 mixed-module mapping, 2022 GOT2 context tests and 2026 linked correction notices sharpen the boundary, but all are published mechanistic or source-integrity work and no running experiment that could cross the next threshold is named; no ongoing recruiting trial is asserted. Momentum corrected from \"Decisive work underway\" to \"Mechanistic only\" on 2026-10-14 in adversarial review by Claude Opus 5.5; momentum modifies no letter.", "justification": "2024 mixed-module mapping, 2022 GOT2 context tests and 2026 linked correction notices sharpen the boundary, but all are published mechanistic or source-integrity work and no running experiment that could cross the next threshold is named; no ongoing recruiting trial is asserted. Momentum corrected from \"Decisive work underway\" to \"Mechanistic only\" on 2026-10-14 in adversarial review by Claude Opus 5.5; momentum modifies no letter." }, "stability": { "value": "Stable", "trigger": "No named pending result is asserted to be likely to move the registered score imminently.", "justification": "No named pending result is asserted to be likely to move the registered score imminently." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "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": "Γ", "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": "Preregister an orthology-robust ancestral edge-defined network, then selectively sever its proposed conserved regulatory edges in autochthonous lineage-matched tumors and growth-matched normal tissues, rescue with edge-specific restoration, and track initiation, maintenance and relapse separately.", "readout": "Single-cell ancestry-aware edge activity, clonal tumor burden/relapse, growth and viability with metabolic flux and target engagement", "critical_control": "Comparable basal replication, normal proliferating lineage, matched nonancestral edges, off-target resistant rescue and alternative rewiring predictions", "supporting_result": "Selective ancestral-network loss consistently removes tumor dependency and matched restoration rescues without simply restoring generic proliferation", "falsifying_result": "Tumors persist after confirmed network interruption, normal proliferating cells fail equally, or new context-dependent edges better predict response" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Define the ancestral network by conserved regulatory edges before tumor outcomes, rather than equating old proteins with a recovered program.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Recompute gene ages with orthology/detection-error robustness and matched proliferating normal lineages.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Use single-cell lineage/composition controls so bulk normal differentiation loss is separated from UC activation.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Separate single-gene essentiality from coherent program-selective loss and matched rescue preserving basal proliferation.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Prospectively test ordered serial metabolism with identifiable flux/ATP models; cross-sectional states are not chronological regressions.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Map residual, metastatic and treatment-selected oxidation without redefining the historical sequence after observing it.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Replicate distinctive network perturbation across independent tumor contexts with initiation, maintenance and relapse endpoints.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Complete current correction/figure audits, including unavailable details of the 2026 residual-cell correction, before reusing those figures publicly.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-08", "reviewer": "Codex", "evidence_base_note": "59 primary reports; literature cutoff 2026-10-08; source examination UTC date 2026-10-08; 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. SciSpace discovery was also used; matched primary leads were resolved to original records before counting. See scispace-leads.json.", "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 network perturbation, somatic natural experiments, longitudinal clonal dependency, selective rescue and independent cancer-lineage replication are live upper-level equivalents. They need not be RCTs, but none here establishes the distinctive ancestry-defined coherent program." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Endogenous genetic network perturbation, somatic natural experiments, longitudinal clonal dependency, selective rescue and independent cancer-lineage replication are live upper-level equivalents. They need not be RCTs, but none here establishes the distinctive ancestry-defined coherent program." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Endogenous genetic network perturbation, somatic natural experiments, longitudinal clonal dependency, selective rescue and independent cancer-lineage replication are live upper-level equivalents. They need not be RCTs, but none here establishes the distinctive ancestry-defined coherent program." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Endogenous genetic network perturbation, somatic natural experiments, longitudinal clonal dependency, selective rescue and independent cancer-lineage replication are live upper-level equivalents. They need not be RCTs, but none here establishes the distinctive ancestry-defined coherent program." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Endogenous genetic network perturbation, somatic natural experiments, longitudinal clonal dependency, selective rescue and independent cancer-lineage replication are live upper-level equivalents. They need not be RCTs, but none here establishes the distinctive ancestry-defined coherent program." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 59, "claims_total": 64, "claims_verified": 64, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 59, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Seven TCGA tumor types, 3473 tumors/386 normals and 17318 aged genes show UC-biased expression and disrupted UC-MC coexpression; twelve hub regulators are proposed. Both normal and tumor tissue co-regulate ancient processes; not all UC processes rise. Bulk growth/composition and shared orthology assignments remain; no ancestral-program reconstitution.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph49, 0:Publisher HTML paragraphs:paragraph50. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C2", "text": "Thirty solid cancer types connect mutation/CNA strata to UC-MC regulatory links; 364 Avana cell-line CRISPR screens and 250-drug data inform dependency/response associations. There is genuine single-gene perturbation data, but no selective unified ancestral network subtraction/rescue or endogenous in vivo program dependency; pooled regulator contrasts are not randomized installation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Materials and methods:paragraph0, 3:Materials and methods:paragraph1, 3:Materials and methods:paragraph11, 3:Materials and methods:paragraph12, 3:Materials and methods:paragraph16, 3:Materials and methods:paragraph25, 3:Materials and methods:paragraph27. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C3", "text": "31 cancer types and 16 matched-normal cohorts show novel mixed UC-MC WGCNA modules, CNA associations and grade/stage differences. Coexpression is not directed regulation; novel combinations argue against a simply restored intact network but do not disprove every partial-atavism definition. LGG/GBM class contrasts are not observed individual progression.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph9, 1:Results:paragraph12, 1:Results:paragraph24, 1:Results:paragraph26, 1:Results:paragraph31. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C4", "text": "Original homology analysis identifies a prokaryotic metabolic toolbox among cancer-related human proteins. Conserved protein ancestry does not specify a preserved ancestral regulatory program or its causal role in tumors.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C5", "text": "Whole-genome-duplication analysis of 1474 genes and cancer proteomics finds ancient and later placentation/cancer-testis enrichments. Mixed evolutionary origins and network annotation are compatible with selective reuse; neither causal program execution nor uniformly pre-metazoan identity follows.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C6", "text": "Simulations show homology-detection error can bias inferred gene ages and expression-age trends. Synthetic detection bias does not show all cancer age patterns are artifacts; linked erratum PMID27738272 details were not accessible for examination.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C7", "text": "Further simulations and empirical-method assessment identify systematic phylostratigraphic errors. A disputed methodological result is not direct tumor causality evidence; robustness should be tested on the actual cancer gene sets.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C8", "text": "Reanalysis argues reported patterns withstand estimated BLAST false-negative rates of 11–15 percent. Methodological rebuttal is retained; persistence of a trend does not establish an ancestral driver, and cancer-specific proliferation controls are separate.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C9", "text": "Alternative homology tools and error-prediction benchmarks fail to eliminate age-estimation bias; removal can erase or reverse tested trends. Results concern tested benchmarks, not a definitive refutation of every tumor phylostratigraphic association.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C10", "text": "Defined hTERT, SV40 early-region and RAS expression historically transformed human cells. 2026 Expression of Concern PMID41986727 concerns possible duplicated Fig1b bands with unavailable raw data; editors retain other support. Kept as examined historical context, excluded from load-bearing positive adjudication.", "carries_number": true, "load_bearing_for": [ "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": "2026-10-08", "note": "" }, { "id": "C11", "text": "SV40 elements disrupting pRB, p53 and PP2A cooperate with telomerase/RAS in human transformation. Engineered viral/cell-line model and shared Hahn platform; linked erratum has no supplied PMID and unexamined details. Constraint disruption does not distinguish flexible partial atavism by itself.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "2026-10-08", "note": "" }, { "id": "C12", "text": "Stepwise p53/INK4A/RAS/hTERT manipulations produce transformation-associated expression shifts. Installed elements and signatures do not isolate an ancestral network; engineered fibroblasts cannot establish general human initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C13", "text": "Conditional K-RASG12D expression induces tumors in basal epithelium within 10–20 days. Forced expression proves regulator capability in that tissue, not the absence of all downstream evolutionary reuse.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "2026-10-08", "note": "" }, { "id": "C14", "text": "Defined elements transform FTSEC, including viral-free p53/CDK4/PP2A changes with hTERT/MYC. Cultured/xenografted installation is bounded; does not reconstruct or subtract a coherent ancestral program.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "2026-10-08", "note": "" }, { "id": "C15", "text": "PAX3-FOXO1/MYCN supports tumor initiation/maintenance; withdrawal regresses tumors but some recur fusion independently. Immortalized xenograft context; recurrence demonstrates plasticity rather than universal addiction or a universal ancestral route.", "carries_number": true, "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": "2026-10-08", "note": "" }, { "id": "C16", "text": "Switching MYC off regresses hematopoietic tumors with apoptosis/differentiation. Conditional transgene model; MYC necessity here does not logically exclude a required downstream ancestral module.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "2026-10-08", "note": "" }, { "id": "C17", "text": "Brief MYC inactivation permits sustained differentiation; reactivation induces apoptosis in this model. Tissue-specific response differs from other MYC systems; no whole ancestral-network test.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "2026-10-08", "note": "" }, { "id": "C18", "text": "MYC withdrawal produces differentiated dormant tumor-derived liver/biliary cells; reactivation restores tumors. Dormancy and reactivation differ from irreversible osteosarcoma reversion; conditional model not broad human primacy.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "2026-10-08", "note": "" }, { "id": "C19", "text": "Brief MYC shutdown is insufficient for durable islet/skin reversion, with recurrence influenced by Bcl-xL/context. A context boundary for regulator dependence, not proof of a single ancient fallback route.", "carries_number": false, "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": "2026-10-08", "note": "" }, { "id": "C20", "text": "MYC-transgene withdrawal regresses lymphoma; genomic instability and transgene-related selection accompany recurrence. Related MYC platforms are not independent biological replications for each paper; selection does not prove program ancestry.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C21", "text": "Recurrent tumors restore MYC signaling through tTA mutation/endogenous MYC/Notch, with MYC knockdown dependency. Restoration through alternative routes supports selected dependency, not universal MYC necessity or ancestral-program independence.", "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": "2026-10-08", "note": "" }, { "id": "C22", "text": "KRAS maintains pancreatic tumors and controls anabolic glucose/nonoxidative PPP use. Conditional oncogene setting; metabolic reprogramming is not a measured evolutionary sequence.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C23", "text": "After KRAS withdrawal, residual cells show respiratory dependence, poor glycolytic compensation and oligomycin-sensitive sphere/regrowth readouts; one of four treated animals remained relapse-free beyond 60 days. Selected model, pleiotropic drug and small in vivo arm; correction PMID41951747 (2026) lists corrected Fig4a but full notice was unavailable. Not load-bearing alone or fully current figure audit.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Main text:paragraph1, 2:Main text:paragraph3, 2:Main text:paragraph6, 2:Main text:paragraph7, 2:Main text:paragraph10, 2:Main text:paragraph16. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C24", "text": "YAP1/TEAD2/E2F can bypass KRAS dependence in recurrent pancreatic tumors. 2019 correction PMID31730860 replaces a wrong GFP image in Fig4C; independent quantified graphs reportedly unchanged. Shared inducible platform and corrected image limit independence.", "carries_number": true, "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": "2026-10-08", "note": "" }, { "id": "C25", "text": "KRAS ablation kills whereas MEK inhibition is cytostatic; RTK/PI3K compensation motivates combinations. Genetic removal and incomplete downstream pharmacology differ; effects do not establish ancestor-network necessity.", "carries_number": true, "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": "2026-10-08", "note": "" }, { "id": "C26", "text": "KRAS-associated GOT1 glutamine/redox pathway supports cultured growth and tumor assays. Culture/environment and redox pleiotropy; linked erratum details unavailable. Do not treat as universal metabolic dependency.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C27", "text": "GOT2 loss impairs cultured redox/growth but does not impair tested xenograft/autochthonous tumors; CAF pyruvate rescues culture. In vivo failure of pyruvate blocking to sensitize shows additional compensation; null is context-specific, not no metabolic causality.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C28", "text": "KRAS/MAPK/MYC regulates RPIA and nucleotide PPP; intervention affects differential KRAS-sensitive/resistant growth. Pathway-specific selected dependencies do not imply ordered historical metabolic regression.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C29", "text": "Nine NSCLC patients show glycolytic and TCA labeling with perfusion heterogeneity; NMR positional labeling and relative TCA modeling support glucose oxidation. Relative labeling/flux fits are not absolute ATP partitioning; circulating lactate and tissue composition confound simple cellular flux inference.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph3, 1:RESULTS:paragraph5, 1:RESULTS:paragraph7, 1:RESULTS:paragraph8, 1:RESULTS:paragraph11. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C30", "text": "Thirty glucose/five lactate-infused lung-cancer patients show lactate oxidation; MCT1 deletion removes lactate labeling in HCC15 xenografts. Model cannot quantitatively determine net lactate flow; labeled lactate enters other pools. MCT1 knockout preserves culture doubling time: substrate uptake is not demonstrated growth necessity.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph7, 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph15, 1:Results:paragraph16. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C31", "text": "IACS complex-I inhibition reduces glucose/lactate TCA contributions and increases glutamine; yeast NDI1 NADH-oxidation rescue normalizes relevant labeling. TCA labeling alone does not measure ETC before perturbation; selective model rescue does not establish a universal tumor respiratory fraction.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C32", "text": "23 tumors from 22 children show glycolytic/TCA glucose metabolism, with PDH predominant in the studied set. Restricted diagnoses and intraoperative infusion; labeling does not establish evolutionary ordering or absolute ATP.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C33", "text": "52 untreated NSCLC tumors show FDG avidity related to proliferation/alternative substrate use rather than a simple glucose-label glycolysis relation. FDG trapping and isotope enrichment test different processes; no direct whole-program perturbation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C34", "text": "RAS-driven lung tumors require pyruvate oxidation in vivo and use less glutamine than cultured counterparts. Model-specific endogenous dependence and culture mismatch; not a universal lung/metastatic metabolism claim.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C35", "text": "EGF-versus-KRASG12V proliferation matching explains most metabolic shifts in immortalized 184A1 cells; several KRAS-associated fluxes are lower at matched growth. Growth matching is a useful rival control, not direct validation of all TCGA gene-age associations or intact normal tissue physiology.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph10, 1:Results:paragraph11, 1:Results:paragraph12. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C36", "text": "PDH activation limits growth through NADH accumulation; uncoupling/ATP hydrolysis can restore NAD balance and proliferation. Aerobic glycolysis can serve redox demands rather than respiratory absence; culture manipulations do not establish whole-tumor universality.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C37", "text": "Tumors show glycolysis, oxidative PPP-derived ribose and TCA amino-acid contributions, with lactate exchange differing from lung tumors. Tumor-type heterogeneity rather than a longitudinal evolutionary series; labels are not absolute ATP fractions.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C38", "text": "Flux, protein synthesis and cell-size comparisons relate metabolism to proliferation across NCI60. Cell-line panel/compositional scaling cannot separate all tissue/genotype effects or infer an ancestral network.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C39", "text": "ERBB2/EGFR/PI3K restores detached-cell glucose/PPP support; antioxidant rescue enables fatty-acid oxidation without restoring glucose uptake. Context/pleiotropy and culture assays; survival rescue is not coherent ancient-program reconstitution.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C40", "text": "Function-blocking beta1-integrin antibodies/Fab revert malignant 3D phenotypes; washout restores malignancy, and brief pretreatment lowers xenograft nodules. Reversible single-line tissue signaling context; not universal genotype independence or reversion of all malignancy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph7. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C41", "text": "Brief compression yields more normal acini with NO-dependent response. Physical context and selected 3D readouts, not endogenous in vivo cancer eradication or ancestry-specific perturbation.", "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": "2026-10-08", "note": "" }, { "id": "C42", "text": "cAMP/PI3K/fibronectin interventions alter malignant organization and chromatin accessibility. Related HMT model platform; pleiotropic reversion does not establish restoration of an intact ancestral or metazoan network.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C43", "text": "Tree-based network reconstruction identifies differing routes and compensations in reverted HMT phenotypes. Same series/model as prior 3D studies, with inferred edges rather than independent endogenous causal replication.", "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": "2026-10-08", "note": "" }, { "id": "C44", "text": "SOX9 boosts proliferation without hyperplasia alone, enhances Pten-associated PIN and is attenuated by knockout. A metazoan developmental pathway can contribute without sufficiency; context-specific genetic interaction.", "carries_number": true, "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": "2026-10-08", "note": "" }, { "id": "C45", "text": "Colon cancers share 8–19 percent of fetal intestinal signatures compared with 1–6 percent in other tissues. Developmental lineage similarity is not pre-metazoan program identity or causal dependency.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C46", "text": "Androgen-induced embryonic prostate programs are enriched in lethal prostate tumors. Metazoan lineage-program overlap and association; no selective driver subtraction/rescue.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C47", "text": "Hand2 loss affects mesothelial development; reactivation is observed in mesothelioma. Developmental loss-of-function is not tumor Hand2 necessity, and reactivation is of a later multicellular program.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C48", "text": "SOX11/4 embryonic-state induction and knockout influence normal repair through targets including fascin. Physiological embryonic reuse can occur without cancer; normal repair comparator is not tumor-program disproof.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C49", "text": "Four renal tumors show branched regional evolution with 63–69 percent of somatic alterations not shared across regions. Heterogeneity does not exclude a conserved underlying program; linked erratum details unavailable and no ancestral-state perturbation.", "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": "2026-10-08", "note": "" }, { "id": "C50", "text": "TRACERx 1644 regions from 421 patients documents branching, whole-genome duplication and subclonal selection associated with relapse. 2024 correction swaps death/censor symbols in Fig1; original notice examined. Clonal selection is not itself proof against all ancient cellular modules.", "carries_number": true, "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": "2026-10-08", "note": "" }, { "id": "C51", "text": "Five primary/liver-metastasis cases show branched genetic heterogeneity. Small observational phylogeny cannot identify a specific regulatory mechanism or exclude a shared function.", "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": "2026-10-08", "note": "" }, { "id": "C52", "text": "Eleven cases show early branching among precursor, primary and metastatic lesions. Timing/branching inference is not direct ancestor-program activity or causal removal.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-08", "note": "" }, { "id": "C53", "text": "Thirty samples from eight patients exhibit parallel, linear and branched routes. Multiple routes constrain a rigid trajectory but are not direct tests of all atavism variants.", "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": "2026-10-08", "note": "" }, { "id": "C54", "text": "MCT1 perturbation reduces metastasis without equivalent primary-growth effects; antioxidants rescue selected readouts. Relapse/metastatic metabolism differs from primary growth and culture uptake; transplantation context limits generality.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C55", "text": "Stem-like cells show greater oxidative capacity and less lactate than differentiated counterparts; irradiation alters states. Marker/culture selection does not establish a stable endogenous hierarchy or ordered backward evolution.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C56", "text": "AS30D hepatoma respiration/oligomycin analyses estimate predominantly oxidative ATP production. Single cell model and ATP estimation assumptions; does not quantify all human cancers.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C57", "text": "Quiescent glioma stem-like populations have low glycolytic and oxidative rates with metabolic heterogeneity after irradiation. Cultured selection and state-specific output, not generalized tumor-wide respiratory failure or a serial evolutionary order.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C58", "text": "HDAC inhibition lowers MYC and raises PGC1/PPAR-linked FAO/OXPHOS; combined FAO/HDAC intervention improves tested tumor-model survival. Drug pleiotropy and selected settings; induced forward adaptation fits metabolic plasticity without ancestry-specific identification.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C59", "text": "45-patient CLL cohort shows variable respiration linked to prognosis; BCR/PI3K perturbation reduces OCR and ECAR. Ex vivo signaling and association do not establish universal respiratory dependency or evolutionary ordering.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC1", "text": "Β: ancient-expression and coexpression patterns are human associations, with a real methods debate and incomplete matched-normal proliferation controls.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 33, 35, 38, 45, 46, 48 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC2", "text": "Γ: network/mutation/dependency integration supplies mechanistic plausibility and culture perturbations, but not recovery, selective subtraction or rescue of a predeclared coherent ancestral program. New mixed modules favor rewiring.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC3", "text": "Γ: functional regulator and metabolic dependencies exist, but no program-specific endogenous in vivo initiation/maintenance/relapse dependence establishes the nominal driver.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 34, 39, 40, 41, 42, 43, 44, 49, 50, 51, 52, 53, 54, 58, 59 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC4", "text": "Β: metabolic state associations are heterogeneous; retained oxidation and treatment-selected respiratory states constrain serial regression, and no registered longitudinal evolutionary order was tested.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 22, 23, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 54, 55, 56, 57, 58, 59 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CH", "text": "Ancient gene use and regulatory disruption are supported, but an intact pre-existing ancestral program has not been shown to drive cancer; tumor-specific rewiring and metabolic plasticity remain stronger explanations.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 35, 29 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-08", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Trigos AS, Pearson RB, Papenfuss AT et al. Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors. Proceedings of the National Academy of Sciences of the United States of America. 2017.", "tier": "A", "kind": "primary", "pmid": "28484005", "doi": "10.1073/pnas.1617743114", "url": "https://pubmed.ncbi.nlm.nih.gov/28484005/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28484005", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph49, 0:Publisher HTML paragraphs:paragraph50. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 2, "citation": "Trigos AS, Pearson RB, Papenfuss AT et al. Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer. eLife. 2019.", "tier": "A", "kind": "primary", "pmid": "30803482", "doi": "10.7554/eLife.40947", "url": "https://pubmed.ncbi.nlm.nih.gov/30803482/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30803482", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Materials and methods:paragraph0, 3:Materials and methods:paragraph1, 3:Materials and methods:paragraph11, 3:Materials and methods:paragraph12, 3:Materials and methods:paragraph16, 3:Materials and methods:paragraph25, 3:Materials and methods:paragraph27. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 3, "citation": "Trigos AS, Bongiovanni F, Zhang Y et al. Disruption of metazoan gene regulatory networks in cancer alters the balance of co-expression between genes of unicellular and multicellular origins. Genome biology. 2024.", "tier": "A", "kind": "primary", "pmid": "38685127", "doi": "10.1186/s13059-024-03247-1", "url": "https://pubmed.ncbi.nlm.nih.gov/38685127/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID38685127", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph9, 1:Results:paragraph12, 1:Results:paragraph24, 1:Results:paragraph26, 1:Results:paragraph31. 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