{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Genome Instability: Root Cause vs Consequence", "entry_form": "phenomenon", "gradeable_restatement": "Ongoing genome instability is the primary root cause of cancer initiation and malignant progression rather than a consequence of oncogenic transformation or a context-dependent accelerator.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Initiation, maintenance, metastasis, mutation process, segregation rate, lineage and genotype distinguished prospectively", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Genome Instability: Root Cause vs Consequence", "central_claim": "Ongoing genome instability is the primary root cause of cancer initiation and malignant progression rather than a consequence of oncogenic transformation or a context-dependent accelerator.", "proposed_mechanism": "Ongoing genome instability is the primary root cause of cancer initiation and malignant progression rather than a consequence of oncogenic transformation or a context-dependent accelerator.", "claimed_scope": "Ongoing genome instability is the primary root cause of cancer initiation and malignant progression rather than a consequence of oncogenic transformation or a context-dependent accelerator.", "claimed_level": [ "etiology", "progression" ], "is_conjunctive": true, "conjunctive_note": "Ranking labels this entry Cancer Biology. The index genome-instability entry instead concerns aging; that scope is not silently imported. Distinguish instability rate from fixed driver mutations, repair-deficiency initiation from acquired chromosomal instability, and contributing evolution from universal primacy." }, "rubric_routing": { "primary_rubric": "02-cancer-biology.md", "secondary_rubrics": [], "index_notes_applied": [ "Ranking labels this entry Cancer Biology. The index genome-instability entry instead concerns aging; that scope is not silently imported. Distinguish instability rate from fixed driver mutations, repair-deficiency initiation from acquired chromosomal instability, and contributing evolution from universal primacy." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Genome instability occurs in established cancers.", "subclaim_type": "existence", "scope": "tumor lineage, stage and measured mutation/segregation rate", "claimed_scope": "tumor lineage, stage and measured mutation/segregation rate", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Longitudinal rate measurement rather than copy-number burden alone", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Tumor genomes and direct cell-division assays establish that changing genomes exist; mere occurrence is descriptive under the causal rubric. Burden, frequency and inferred historical process are distinguished from per-division rate." }, { "id": "SC2", "statement": "Endogenous repair/segregation defects can initiate cancers.", "subclaim_type": "sufficiency", "scope": "specific lesion and tissue genotype", "claimed_scope": "specific lesion and tissue genotype", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Endogenous lesion with incidence and matched restoration", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Endogenous MMR, repair-domain and segregation-gene models, normal-tissue mutator measurements and cell repair complementation converge on defined susceptibility. Gene pleiotropy, cooperating drivers and tissue-specific negative outcomes bound the conclusion; susceptibility is not immediate sole transformation." }, { "id": "SC3", "statement": "Ongoing instability contributes to progression or metastasis.", "subclaim_type": "mechanism", "scope": "instability subtype, stage and rate defined before outcome", "claimed_scope": "instability subtype, stage and rate defined before outcome", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Selective rate reduction/restoration and clone-resolved behavior", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Measured rate correction changes metastasis independently of karyotypic burden, and CIN manipulations alter resistance and recurrence in specified oncogene/treatment models. Most interventions are engineered or transplant based; host dependence, shared programmes and lack of matched independent autochthonous rate-restoration course tests prevent a field-wide upper grade." }, { "id": "SC4", "statement": "Genome instability is the general primary root cause of cancer.", "subclaim_type": "primacy", "scope": "representative prespecified cancer etiologies and stages", "claimed_scope": "representative prespecified cancer etiologies and stages", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Paired instability/driver perturbations with causal temporal ordering", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Mechanistic and in vivo causal contributions make a broad instability-first model plausible, but no matching evidence establishes general primacy over upstream oncogenes or context-dependent amplification. Negative endogenous models and transient initiation with continued tumor growth distinguish contribution from obligatory ongoing root." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "Ranking labels this entry Cancer Biology. The index genome-instability entry instead concerns aging; that scope is not silently imported. Distinguish instability rate from fixed driver mutations, repair-deficiency initiation from acquired chromosomal instability, and contributing evolution from universal primacy.", "primary_subclaim_id": "SC4", "aggregation_derivation": "The preregistered general-root gate SC4 remains Γ. Endogenous repair and segregation perturbations establish defined cancer-susceptibility routes (SC2 Ζ), and rate-specific progression or resistance interventions support context-valid causality (SC3 Ε). Associations and fixed abnormal states cannot establish the temporal root of all cancer.", "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": "M3", "is_nominal": false, "name": "Context-dependent evolutionary accelerator", "core_claim": "Instability supplies selectable diversity or signaling in already susceptible or oncogene-driven tumors.", "explains_what_nominal_does_not": "Instability supplies selectable diversity or signaling in already susceptible or oncogene-driven tumors.", "strongest_supporting_evidence": [ "Rate correction with retained aneuploid burden, resistance contrasts and recurrence models discriminate stage-specific roles (PMID29342134,35905505,20173739)." ], "strongest_contradictory_evidence": [ "This winner is scoped to tested progression and selection settings, not a new universal origin." ], "hsef_level_for_this_model": "Ε", "rationale": "Rate correction with retained aneuploid burden, resistance contrasts and recurrence models discriminate stage-specific roles (PMID29342134,35905505,20173739). This winner is scoped to tested progression and selection settings, not a new universal origin." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Oncogene-first stress with barrier escape", "core_claim": "Upstream oncogenic activity creates replication/segregation stress, and checkpoint barriers determine survival.", "explains_what_nominal_does_not": "Upstream oncogenic activity creates replication/segregation stress, and checkpoint barriers determine survival.", "strongest_supporting_evidence": [ "RAS/MAPK and HER2 interventions, early damage responses and ATM-barrier disruption establish this direction in defined models (PMID10951588,27634334,17136093)." ], "strongest_contradictory_evidence": [ "Culture and engineered models do not determine the fraction of human sporadic initiation attributable to this route." ], "hsef_level_for_this_model": "Ε", "rationale": "RAS/MAPK and HER2 interventions, early damage responses and ATM-barrier disruption establish this direction in defined models (PMID10951588,27634334,17136093). Culture and engineered models do not determine the fraction of human sporadic initiation attributable to this route." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Genome-stress immune signaling", "core_claim": "Cytosolic DNA changes tumor and host immune states with context-dependent consequences.", "explains_what_nominal_does_not": "Cytosolic DNA changes tumor and host immune states with context-dependent consequences.", "strongest_supporting_evidence": [ "STING epistasis and immune-competent versus deficient hosts support specific pathways (PMID37612508,33372007,33338425)." ], "strongest_contradictory_evidence": [ "CIN-associated immunosuppression and MMR-linked immune rejection differ; pathway activation alone does not imply a universal outcome." ], "hsef_level_for_this_model": "Ε", "rationale": "STING epistasis and immune-competent versus deficient hosts support specific pathways (PMID37612508,33372007,33338425). CIN-associated immunosuppression and MMR-linked immune rejection differ; pathway activation alone does not imply a universal outcome." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Rate-dependent fitness and tumor barrier", "core_claim": "Excess instability or stress can impair viability and tumor progression.", "explains_what_nominal_does_not": "Excess instability or stress can impair viability and tumor progression.", "strongest_supporting_evidence": [ "Measured CENP-E/Mad2 high-error contrasts and independent INO80/Apc fork-stress course changes support bounded suppressive mechanisms (PMID24133140,27146113,29383140)." ], "strongest_contradictory_evidence": [ "These are independent error families but not a universal quantitative threshold; low and high rates, mutation classes and tissues differ." ], "hsef_level_for_this_model": "Ζ", "rationale": "Measured CENP-E/Mad2 high-error contrasts and independent INO80/Apc fork-stress course changes support bounded suppressive mechanisms (PMID24133140,27146113,29383140). These are independent error families but not a universal quantitative threshold; low and high rates, mutation classes and tissues differ." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "General instability-first root", "core_claim": "Instability can precede and enable transforming changes.", "explains_what_nominal_does_not": "Instability can precede and enable transforming changes.", "strongest_supporting_evidence": [ "Inherited endogenous repair defects and forced mitotic perturbations support genuine initiating capacities (PMID7628020,28132847)." ], "strongest_contradictory_evidence": [ "Capacities and susceptibility do not establish general primacy, continued necessity or all-context sufficiency." ], "hsef_level_for_this_model": "Γ", "rationale": "Inherited endogenous repair defects and forced mitotic perturbations support genuine initiating capacities (PMID7628020,28132847). Capacities and susceptibility do not establish general primacy, continued necessity or all-context sufficiency." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Silk rate-stratified endogenous contrasts, Levine versus Vitre centrosome models and transient CIN/p53 stratification separate generalized instability-first claims from context-dependent promotion, suppression or no change (PMID24133140,28132847,26578792,34266887).", "study_separating_rank1_from_rank2": "Silk rate-stratified endogenous contrasts, Levine versus Vitre centrosome models and transient CIN/p53 stratification separate generalized instability-first claims from context-dependent promotion, suppression or no change (PMID24133140,28132847,26578792,34266887).", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "37612508", "title": "Non-cell-autonomous cancer progression from chromosomal instability.", "citation": "Li J, Hubisz MJ, Earlie EM et al. Non-cell-autonomous cancer progression from chromosomal instability. Nature. 2023.", "doi": "10.1038/s41586-023-06464-z", "pmcid": "PMC10468402", "url": "https://pubmed.ncbi.nlm.nih.gov/37612508/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37612508/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37612508", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Immune dependence of CIN-driven metastasis, 6:STING inhibitors suppress metastasis. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Syngeneic mouse and human tumor correlation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "CIN rate and cGAS-STING/ER-stress perturbations alter metastasis through host immune context.", "what_it_does_not_show": "Same Bakhoum programme as 2018; engineered transplant models establish progression not all-cancer initiation.", "confounders_present": [ "Same Bakhoum programme as 2018; engineered transplant models establish progression not all-cancer 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": [ "Bakhoum/Li/ENPP1 programme and model/assay families." ] }, { "n": 2, "pmid": "29342134", "title": "Chromosomal instability drives metastasis through a cytosolic DNA response.", "citation": "Bakhoum SF, Ngo B, Laughney AM et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018.", "doi": "10.1038/nature25432", "pmcid": "PMC5785464", "url": "https://pubmed.ncbi.nlm.nih.gov/29342134/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29342134/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29342134", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:CIN is a driver of metastasis, 3:CIN generates cytosolic DNA, 4:Metastasis from cytosolic DNA response. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Human cell lines and orthotopic/injection mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "KIF2B/MCAK lower measured missegregation without normalizing aneuploid burden; metastasis falls and Mad2 partially restores it.", "what_it_does_not_show": "Primary growth does not consistently fall; forced rate correction and transplantation do not establish universal endogenous initiation.", "confounders_present": [ "Primary growth does not consistently fall; forced rate correction and transplantation do not establish universal endogenous 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": [ "Bakhoum/Li/ENPP1 programme and model/assay families." ] }, { "n": 3, "pmid": "33372007", "title": "Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis.", "citation": "Li J, Duran MA, Dhanota N et al. Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis. Cancer discovery. 2021.", "doi": "10.1158/2159-8290.CD-20-0387", "pmcid": "PMC8102348", "url": "https://pubmed.ncbi.nlm.nih.gov/33372007/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33372007/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33372007", "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": "Strong", "system": "Syngeneic models and patient associations", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "ENPP1 loss and host STING epistasis link extracellular cGAMP handling to metastasis and immune recruitment.", "what_it_does_not_show": "Downstream immune mechanism rather than proof that CIN initiates cancer; shared programme.", "confounders_present": [ "Downstream immune mechanism rather than proof that CIN initiates cancer; shared programme." ], "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": [ "Bakhoum/Li/ENPP1 programme." ] }, { "n": 4, "pmid": "32879494", "title": "Pervasive chromosomal instability and karyotype order in tumour evolution.", "citation": "Watkins TBK, Lim EL, Petkovic M et al. Pervasive chromosomal instability and karyotype order in tumour evolution. Nature. 2020.", "doi": "10.1038/s41586-020-2698-6", "pmcid": "PMC7611706", "url": "https://pubmed.ncbi.nlm.nih.gov/32879494/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32879494/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32879494", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Multi-region human tumors", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Phased copy-number evolution supports ongoing and parallel alteration histories.", "what_it_does_not_show": "Historical inference from sampled genomes is not directly measured per-division missegregation or initiating perturbation; cohort overlap.", "confounders_present": [ "Historical inference from sampled genomes is not directly measured per-division missegregation or initiating perturbation; cohort overlap." ], "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": [ "TRACERx-derived specimens within multi-cohort analysis." ] }, { "n": 5, "pmid": "40670783", "title": "Ongoing genome doubling shapes evolvability and immunity in ovarian cancer.", "citation": "McPherson A, Vázquez-García I, Myers MA et al. Ongoing genome doubling shapes evolvability and immunity in ovarian cancer. Nature. 2025.", "doi": "10.1038/s41586-025-09240-3", "pmcid": "PMC12390843", "url": "https://pubmed.ncbi.nlm.nih.gov/40670783/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40670783/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40670783", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human ovarian single-cell genomes and imaging", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Whole-genome-doubling trajectories and imaging reveal heterogeneous ongoing instability states.", "what_it_does_not_show": "Selected human tumors; temporal reconstruction and immune-state associations do not establish initiating primacy.", "confounders_present": [ "Selected human tumors; temporal reconstruction and immune-state associations do not establish initiating 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": 6, "pmid": "27146113", "title": "High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation.", "citation": "Zasadil LM, Britigan EM, Ryan SD et al. High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation. Molecular biology of the cell. 2016.", "doi": "10.1091/mbc.E15-10-0747", "pmcid": "PMC4927272", "url": "https://pubmed.ncbi.nlm.nih.gov/27146113/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27146113/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27146113", "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": "ApcMin mice and intestinal organoids", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "High chromosome missegregation suppresses later progression while permitting initiating organoids.", "what_it_does_not_show": "Rate and stage dependent; shared CENP-E programme, not evidence against every low-rate contribution.", "confounders_present": [ "Rate and stage dependent; shared CENP-E programme, not evidence against every low-rate contribution." ], "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": [ "CENP-E/Weaver/Silk/Zasadil shared model family." ] }, { "n": 7, "pmid": "24133140", "title": "Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors.", "citation": "Silk AD, Zasadil LM, Holland AJ et al. Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors. Proceedings of the National Academy of Sciences of the United States of America. 2013.", "doi": "10.1073/pnas.1317042110", "pmcid": "PMC3816416", "url": "https://pubmed.ncbi.nlm.nih.gov/24133140/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24133140/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24133140", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph31, 0:Publisher HTML paragraphs:paragraph32, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph35, 0:Publisher HTML paragraphs:paragraph36, 0:Publisher HTML paragraphs:paragraph37, 0:Publisher HTML paragraphs:paragraph38, 0:Publisher HTML paragraphs:paragraph40, 0:Publisher HTML paragraphs:paragraph50. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Endogenous CENP-E/Mad2 mouse contrasts", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "Combined high missegregation raises cell death and reduces tumors; extra CENP-E-dependent CIN has no tumor effect in Ink4a or MLH1 contexts.", "what_it_does_not_show": "Genetic background, rate and tissue matter; this discriminating negative does not enter a positive-support tally.", "confounders_present": [ "Genetic background, rate and tissue matter; this discriminating negative does not enter a positive-support tally." ], "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": [ "CENP-E/Weaver/Silk/Zasadil shared model family." ] }, { "n": 8, "pmid": "23187126", "title": "USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis.", "citation": "Zhang Y, Foreman O, Wigle DA et al. USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis. The Journal of clinical investigation. 2012.", "doi": "10.1172/JCI63084", "pmcid": "PMC3533537", "url": "https://pubmed.ncbi.nlm.nih.gov/23187126/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23187126/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID23187126", "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": "Endogenous USP44-null mice and cells", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "USP44 loss causes segregation defects and spontaneous lung tumors; centrin interaction separates centrosome positioning from checkpoint delay.", "what_it_does_not_show": "USP44 has multiple functions; endogenous model supports a defined initiating route, not a general root.", "confounders_present": [ "USP44 has multiple functions; endogenous model supports a defined initiating route, not a general root." ], "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": "15376262", "title": "Chromosomal instability and APC gene mutations in human sporadic colorectal adenomas.", "citation": "Giaretti W, Venesio T, Prevosto C et al. Chromosomal instability and APC gene mutations in human sporadic colorectal adenomas. The Journal of pathology. 2004.", "doi": "10.1002/path.1623", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15376262/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15376262/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID15376262", "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 colorectal adenomas", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "APC mutation subgroups associate with aneuploid burden.", "what_it_does_not_show": "Overall APC relationship is weak; cross-sectional burden is not a rate measurement or a causal intervention.", "confounders_present": [ "Overall APC relationship is weak; cross-sectional burden is not a rate measurement or a causal intervention." ], "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": "15767571", "title": "Colonic tumorigenesis in BubR1+/-ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability.", "citation": "Rao CV, Yang YM, Swamy MV et al. Colonic tumorigenesis in BubR1+/-ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proceedings of the National Academy of Sciences of the United States of America. 2005.", "doi": "10.1073/pnas.0407822102", "pmcid": "PMC555497", "url": "https://pubmed.ncbi.nlm.nih.gov/15767571/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15767571/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID15767571", "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": "BubR1-haploinsufficient ApcMin mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "BubR1 insufficiency increases chromosome errors and colon tumor incidence and grade with an Apc driver.", "what_it_does_not_show": "Genetic interaction and checkpoint functions are coupled; no claim that instability alone initiates all cancers.", "confounders_present": [ "Genetic interaction and checkpoint functions are coupled; no claim that instability alone initiates all 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": 11, "pmid": "35705807", "title": "A pan-cancer compendium of chromosomal instability.", "citation": "Drews RM, Hernando B, Tarabichi M et al. A pan-cancer compendium of chromosomal instability. Nature. 2022.", "doi": "10.1038/s41586-022-04789-9", "pmcid": "PMC7613102", "url": "https://pubmed.ncbi.nlm.nih.gov/35705807/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35705807/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35705807", "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": "Pan-cancer copy-number signatures", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Copy-number signatures distinguish putative processes across thousands of tumors.", "what_it_does_not_show": "Static patterns and inferred etiologies do not directly measure rates, precedence or necessity.", "confounders_present": [ "Static patterns and inferred etiologies do not directly measure rates, precedence or 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": 12, "pmid": "30675059", "title": "Autophagic cell death restricts chromosomal instability during replicative crisis.", "citation": "Nassour J, Radford R, Correia A et al. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature. 2019.", "doi": "10.1038/s41586-019-0885-0", "pmcid": "PMC6557118", "url": "https://pubmed.ncbi.nlm.nih.gov/30675059/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30675059/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID42321512" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30675059", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human telomere-crisis cell models", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "cGAS-STING/autophagy removes crisis cells; suppressing the barrier permits unstable proliferating cells.", "what_it_does_not_show": "Cell culture and telomere manipulation; linked erratum details unexamined; supports a barrier, not universal tumor suppression.", "confounders_present": [ "Cell culture and telomere manipulation; linked erratum details unexamined; supports a barrier, not universal tumor suppression." ], "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": "34352222", "title": "Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies.", "citation": "Lukow DA, Sausville EL, Suri P et al. Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies. Developmental cell. 2021.", "doi": "10.1016/j.devcel.2021.07.009", "pmcid": "PMC8933054", "url": "https://pubmed.ncbi.nlm.nih.gov/34352222/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34352222/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34352222", "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": "Drug-selected human cell clones and clinical association", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Transient CIN generates recurrent aneuploid resistant clones; a specified chromosome loss confers paclitaxel resistance.", "what_it_does_not_show": "Fixed resistant state is distinct from continued rate dependence; selected treatment context.", "confounders_present": [ "Fixed resistant state is distinct from continued rate dependence; selected treatment context." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "34569598", "title": "TP53 loss initiates chromosomal instability in fallopian tube epithelial cells.", "citation": "Bronder D, Tighe A, Wangsa D et al. TP53 loss initiates chromosomal instability in fallopian tube epithelial cells. Disease models & mechanisms. 2021.", "doi": "10.1242/dmm.049001", "pmcid": "PMC8649171", "url": "https://pubmed.ncbi.nlm.nih.gov/34569598/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34569598/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34569598", "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", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Engineered fallopian epithelial cells", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "p53 loss precedes induced CIN, with BRCA1 and MYC adding instability.", "what_it_does_not_show": "Nontransformed cultures rather than autochthonous initiation; demonstrates a plausible upstream-driver direction.", "confounders_present": [ "Nontransformed cultures rather than autochthonous initiation; demonstrates a plausible upstream-driver direction." ], "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": "38871738", "title": "Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.", "citation": "Hobor S, Al Bakir M, Hiley CT et al. Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling. Nature communications. 2024.", "doi": "10.1038/s41467-024-47606-9", "pmcid": "PMC11176322", "url": "https://pubmed.ncbi.nlm.nih.gov/38871738/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38871738/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38871738", "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": "Strong", "system": "EGFR/TP53 mouse and human lung cancer", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Whole-genome doubling and copy-number routes alter targeted-treatment responses.", "what_it_does_not_show": "Treatment-selected evolution and existing drivers; not untreated initiating primacy.", "confounders_present": [ "Treatment-selected evolution and existing drivers; not untreated initiating 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": 16, "pmid": "41162705", "title": "Origins of chromosome instability unveiled by coupled imaging and genomics.", "citation": "Cosenza MR, Gaiatto A, Erarslan Uysal B et al. Origins of chromosome instability unveiled by coupled imaging and genomics. Nature. 2025.", "doi": "10.1038/s41586-025-09632-5", "pmcid": "PMC12695650", "url": "https://pubmed.ncbi.nlm.nih.gov/41162705/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41162705/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID41162705", "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": "Live mitosis plus single-cell genome assay", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Direct division-to-genome measurements identify new abnormalities and increased rates with TP53 defects.", "what_it_does_not_show": "Near-diploid cultured cells; downstream driver perturbation rather than human initiation.", "confounders_present": [ "Near-diploid cultured cells; downstream driver perturbation rather than 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": 17, "pmid": "36696903", "title": "Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma.", "citation": "Gong Y, Zou S, Deng D et al. Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma. Developmental cell. 2023.", "doi": "10.1016/j.devcel.2022.12.012", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36696903/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36696903/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36696903", "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": "Endogenous mouse osteoprogenitor perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "RanGAP1 dysregulation couples mitotic disruption, chromothripsis, Rb1 disruption and rapid osteosarcoma.", "what_it_does_not_show": "Protein transport, p53 degradation and segregation are coupled; the initiating mechanism is not isolated instability alone.", "confounders_present": [ "Protein transport, p53 degradation and segregation are coupled; the initiating mechanism is not isolated instability alone." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 18, "pmid": "32030896", "title": "Acquisition of chromosome instability is a mechanism to evade oncogene addiction.", "citation": "Salgueiro L, Buccitelli C, Rowald K et al. Acquisition of chromosome instability is a mechanism to evade oncogene addiction. EMBO molecular medicine. 2020.", "doi": "10.15252/emmm.201910941", "pmcid": "PMC7059010", "url": "https://pubmed.ncbi.nlm.nih.gov/32030896/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32030896/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32030896", "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": "Strong", "system": "Kras-dependent breast mouse models", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "CIN promotes escape through MET amplification and creates a new cMet dependency.", "what_it_does_not_show": "Established oncogene-driven and withdrawal-selected disease; not original initiation.", "confounders_present": [ "Established oncogene-driven and withdrawal-selected disease; not original 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": 19, "pmid": "35905505", "title": "Suppression of Chromosome Instability Limits Acquired Drug Resistance.", "citation": "Crowley EA, Hermance NM, Herlihy CP et al. Suppression of Chromosome Instability Limits Acquired Drug Resistance. Molecular cancer therapeutics. 2022.", "doi": "10.1158/1535-7163.MCT-22-0263", "pmcid": "PMC9547972", "url": "https://pubmed.ncbi.nlm.nih.gov/35905505/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35905505/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35905505", "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": "Human NSCLC cells and xenografts", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Reducing CIN changes resistance timing and copy-number routes without changing initial xenograft growth.", "what_it_does_not_show": "Resistance-specific engineered models; transplant growth alone cannot establish endogenous initiating necessity.", "confounders_present": [ "Resistance-specific engineered models; transplant growth alone cannot establish endogenous initiating 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": 20, "pmid": "27930335", "title": "Chromosome instability drives phenotypic switching to metastasis.", "citation": "Gao C, Su Y, Koeman J et al. Chromosome instability drives phenotypic switching to metastasis. Proceedings of the National Academy of Sciences of the United States of America. 2016.", "doi": "10.1073/pnas.1618215113", "pmcid": "PMC5187712", "url": "https://pubmed.ncbi.nlm.nih.gov/27930335/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27930335/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27930335", "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": "Human cultured epithelial/mesenchymal state transitions", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Chromosome-content changes accompany EMT/reversion with ZEB1 functional interventions.", "what_it_does_not_show": "State-selection experiments and transcriptional effects do not isolate ongoing CIN as the sole driver.", "confounders_present": [ "State-selection experiments and transcriptional effects do not isolate ongoing CIN as the sole driver." ], "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": "10608877", "title": "MAPK mediates RAS-induced chromosome instability.", "citation": "Saavedra HI, Fukasawa K, Conn CW et al. MAPK mediates RAS-induced chromosome instability. The Journal of biological chemistry. 1999.", "doi": "10.1074/jbc.274.53.38083", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10608877/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10608877/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID10608877", "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": "RAS-transformed mouse fibroblasts", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "RAS/MAPK activation produces micronuclei, reversed by MEK-pathway inhibition.", "what_it_does_not_show": "Forced expression and cultured cells; upstream oncogene can cause instability but this does not quantify all sporadic tumors.", "confounders_present": [ "Forced expression and cultured cells; upstream oncogene can cause instability but this does not quantify all sporadic 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": 22, "pmid": "37410869", "title": "Oncogene-like addiction to aneuploidy in human cancers.", "citation": "Girish V, Lakhani AA, Thompson SL et al. Oncogene-like addiction to aneuploidy in human cancers. Science (New York, N.Y.). 2023.", "doi": "10.1126/science.adg4521", "pmcid": "PMC10753973", "url": "https://pubmed.ncbi.nlm.nih.gov/37410869/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37410869/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID36711674" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37410869", "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": "Strong", "system": "Human cancer chromosome engineering", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Removing recurrent trisomy 1q impairs malignant growth through an MDM4-p53 axis.", "what_it_does_not_show": "Dependency on a fixed chromosome state is not dependence on the rate of genome change.", "confounders_present": [ "Dependency on a fixed chromosome state is not dependence on the rate of genome change." ], "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": "24121791", "title": "Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy.", "citation": "Balbás-Martínez C, Sagrera A, Carrillo-de-Santa-Pau E et al. Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy. Nature genetics. 2013.", "doi": "10.1038/ng.2799", "pmcid": "PMC3840052", "url": "https://pubmed.ncbi.nlm.nih.gov/24121791/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24121791/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24121791", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Human bladder tumors and STAG2 editing", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "STAG2 loss can affect tumor suppression without aneuploidy or increased aneuploidy after knockdown.", "what_it_does_not_show": "Gene pleiotropy and cancer lineage; repair/segregation gene lesions cannot automatically be assigned to CIN.", "confounders_present": [ "Gene pleiotropy and cancer lineage; repair/segregation gene lesions cannot automatically be assigned to CIN." ], "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": "18974345", "title": "Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells.", "citation": "Williams BR, Prabhu VR, Hunter KE et al. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science (New York, N.Y.). 2008.", "doi": "10.1126/science.1160058", "pmcid": "PMC2701511", "url": "https://pubmed.ncbi.nlm.nih.gov/18974345/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18974345/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID18974345", "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": "Constitutionally trisomic primary mouse cells", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Specified trisomies impair proliferation and alter metabolism.", "what_it_does_not_show": "Static chromosome states and cultured cells; does not negate every adaptive aneuploidy.", "confounders_present": [ "Static chromosome states and cultured cells; does not negate every adaptive aneuploidy." ], "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": "27313317", "title": "Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo.", "citation": "Pfau SJ, Silberman RE, Knouse KA et al. Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo. Genes & development. 2016.", "doi": "10.1101/gad.278820.116", "pmcid": "PMC4926863", "url": "https://pubmed.ncbi.nlm.nih.gov/27313317/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27313317/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27313317", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Aneuploid/CIN hematopoietic stem-cell mice", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Aneuploidy and CIN impair regenerative fitness in vivo.", "what_it_does_not_show": "Regeneration/transplant challenge is not spontaneous tumor initiation; tissue selection boundary.", "confounders_present": [ "Regeneration/transplant challenge is not spontaneous tumor initiation; tissue selection boundary." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 26, "pmid": "21383776", "title": "Fen1 mutations that specifically disrupt its interaction with PCNA cause aneuploidy-associated cancer.", "citation": "Zheng L, Dai H, Hegde ML et al. Fen1 mutations that specifically disrupt its interaction with PCNA cause aneuploidy-associated cancer. Cell research. 2011.", "doi": "10.1038/cr.2011.35", "pmcid": "PMC3129403", "url": "https://pubmed.ncbi.nlm.nih.gov/21383776/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21383776/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21383776", "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": "Endogenous FEN1-domain mutant mice and cells", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Defective PCNA interaction compromises replication/repair and increases instability, transformation and tumors.", "what_it_does_not_show": "Repair, replication and checkpoint functions change together; cell-level Chk1 inhibition is not whole-animal repair restoration.", "confounders_present": [ "Repair, replication and checkpoint functions change together; cell-level Chk1 inhibition is not whole-animal repair restoration." ], "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": "17189716", "title": "Aneuploidy acts both oncogenically and as a tumor suppressor.", "citation": "Weaver BA, Silk AD, Montagna C et al. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer cell. 2007.", "doi": "10.1016/j.ccr.2006.12.003", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17189716/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17189716/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17189716", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "CENP-E-haploinsufficient mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Defined tissues show spontaneous tumor promotion while other contexts show suppression.", "what_it_does_not_show": "Abstract-only; tissue-specific opposing outcomes and shared CENP-E model family limit generalization.", "confounders_present": [ "Abstract-only; tissue-specific opposing outcomes and shared CENP-E model family limit generalization." ], "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": [ "CENP-E shared model family." ] }, { "n": 28, "pmid": "28749464", "title": "The cohesin complex prevents Myc-induced replication stress.", "citation": "Rohban S, Cerutti A, Morelli MJ et al. The cohesin complex prevents Myc-induced replication stress. Cell death & disease. 2017.", "doi": "10.1038/cddis.2017.345", "pmcid": "PMC5550886", "url": "https://pubmed.ncbi.nlm.nih.gov/28749464/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28749464/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28749464", "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": "Cohesin-silenced cells with MYC rescue", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Transcriptional rescue fails to normalize replication stress and S-phase defects.", "what_it_does_not_show": "Cultured cells and cohesin pleiotropy; separates transcription from replication, not general initiation.", "confounders_present": [ "Cultured cells and cohesin pleiotropy; separates transcription from replication, not general 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": 29, "pmid": "27634334", "title": "DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer.", "citation": "Kanu N, Cerone MA, Goh G et al. DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer. Genome biology. 2016.", "doi": "10.1186/s13059-016-1042-9", "pmcid": "PMC5025597", "url": "https://pubmed.ncbi.nlm.nih.gov/27634334/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27634334/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27634334", "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": "HER2/PTEN breast systems", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Oncogenic signaling induces replication stress/APOBEC activity, reduced by RTK inhibition or nucleosides.", "what_it_does_not_show": "Enzyme activity is not a measured longitudinal mutation rate or organismal tumor-course rescue.", "confounders_present": [ "Enzyme activity is not a measured longitudinal mutation rate or organismal tumor-course 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": 30, "pmid": "29383140", "title": "INO80 haploinsufficiency inhibits colon cancer tumorigenesis via replication stress-induced apoptosis.", "citation": "Lee SA, Lee HS, Hur SK et al. INO80 haploinsufficiency inhibits colon cancer tumorigenesis via replication stress-induced apoptosis. Oncotarget. 2017.", "doi": "10.18632/oncotarget.22984", "pmcid": "PMC5777752", "url": "https://pubmed.ncbi.nlm.nih.gov/29383140/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29383140/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29383140", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "INO80-haploinsufficient ApcMin mice", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "Increased fork stress and checkpoint apoptosis reduce polyps and improve survival.", "what_it_does_not_show": "Existing Apc driver and repair-protein pleiotropy; excess instability/stress may suppress rather than initiate.", "confounders_present": [ "Existing Apc driver and repair-protein pleiotropy; excess instability/stress may suppress rather than initiate." ], "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": "33338427", "title": "MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway.", "citation": "Guan J, Lu C, Jin Q et al. MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway. Cancer cell. 2021.", "doi": "10.1016/j.ccell.2020.11.004", "pmcid": "PMC8666006", "url": "https://pubmed.ncbi.nlm.nih.gov/33338427/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33338427/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33338427", "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": "MLH1-deficient cells and models", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Exo1-dependent hyperexcision links MMR loss to cytosolic DNA and STING.", "what_it_does_not_show": "Repair loss can trigger opposing immune consequences; not a universal tumor-promoting root.", "confounders_present": [ "Repair loss can trigger opposing immune consequences; not a universal tumor-promoting root." ], "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": "36584674", "title": "Genetic and pharmacological modulation of DNA mismatch repair heterogeneous tumors promotes immune surveillance.", "citation": "Amodio V, Lamba S, Chilà R et al. Genetic and pharmacological modulation of DNA mismatch repair heterogeneous tumors promotes immune surveillance. Cancer cell. 2023.", "doi": "10.1016/j.ccell.2022.12.003", "pmcid": "PMC9833846", "url": "https://pubmed.ncbi.nlm.nih.gov/36584674/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36584674/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36584674", "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": "Mixed MMR-proficient/deficient immune-competent CRC models", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Increasing the dMMR fraction allows immune rejection in a defined mixture and treatment setting.", "what_it_does_not_show": "Mixture threshold and immune context; does not imply prevention of all MMR-deficient tumors.", "confounders_present": [ "Mixture threshold and immune context; does not imply prevention of all MMR-deficient 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": 33, "pmid": "33338425", "title": "DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity.", "citation": "Lu C, Guan J, Lu S et al. DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity. Cancer cell. 2021.", "doi": "10.1016/j.ccell.2020.11.006", "pmcid": "PMC9477183", "url": "https://pubmed.ncbi.nlm.nih.gov/33338425/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33338425/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33338425", "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": "Strong", "system": "MLH1-deficient mouse tumors", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "cGAS/STING governs priming and checkpoint response in repair-defective tumors.", "what_it_does_not_show": "Downstream immune context and pre-established tumors; greater instability can favor host control.", "confounders_present": [ "Downstream immune context and pre-established tumors; greater instability can favor host control." ], "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": "27436342", "title": "Loss of mutL homolog-1 (MLH1) expression promotes acquisition of oncogenic and inhibitor-resistant point mutations in tyrosine kinases.", "citation": "Springuel L, Losdyck E, Saussoy P et al. Loss of mutL homolog-1 (MLH1) expression promotes acquisition of oncogenic and inhibitor-resistant point mutations in tyrosine kinases. Cellular and molecular life sciences : CMLS. 2016.", "doi": "10.1007/s00018-016-2310-2", "pmcid": "PMC11108519", "url": "https://pubmed.ncbi.nlm.nih.gov/27436342/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27436342/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27436342", "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": "Cell complementation and leukemia association", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "MLH1 manipulation changes resistant mutation frequencies and growth-factor/drug dependence.", "what_it_does_not_show": "Cell restoration plus patient association do not establish prospective human tumor prevention.", "confounders_present": [ "Cell restoration plus patient association do not establish prospective human tumor prevention." ], "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": "11376699", "title": "Tumorigenesis as a consequence of genetic instability in Brca1 mutant mice.", "citation": "Deng CX et al. Tumorigenesis as a consequence of genetic instability in Brca1 mutant mice. Mutation research. 2001.", "doi": "10.1016/s0027-5107(01)00119-1", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11376699/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11376699/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID11376699", "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": "Conditional mammary Brca1 loss", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Endogenous Brca1 loss predisposes mammary tumors with later cooperating alterations.", "what_it_does_not_show": "Long latency and p53 mutations; essential repair, growth and apoptosis functions cannot be reduced to one rate.", "confounders_present": [ "Long latency and p53 mutations; essential repair, growth and apoptosis functions cannot be reduced to one rate." ], "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": "11861370", "title": "Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene.", "citation": "McAllister KA, Bennett LM, Houle CD et al. Cancer susceptibility of mice with a homozygous deletion in the COOH-terminal domain of the Brca2 gene. Cancer research. 2002.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11861370/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11861370/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID11861370", "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": "Brca2 domain-mutant mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Viable homozygous domain-mutant animals develop more tumors and shorter survival.", "what_it_does_not_show": "Domain perturbation has coupled functions; no genotype-matched full repair restoration establishes all-cancer primacy.", "confounders_present": [ "Domain perturbation has coupled functions; no genotype-matched full repair restoration establishes all-cancer primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 37, "pmid": "17189715", "title": "Mad2 overexpression promotes aneuploidy and tumorigenesis in mice.", "citation": "Sotillo R, Hernando E, Díaz-Rodríguez E et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer cell. 2007.", "doi": "10.1016/j.ccr.2006.10.019", "pmcid": "PMC1850996", "url": "https://pubmed.ncbi.nlm.nih.gov/17189715/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17189715/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17189715", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph15, 0:Publisher HTML paragraphs:paragraph22, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph27, 0:Publisher HTML paragraphs:paragraph29, 0:Publisher HTML paragraphs:paragraph30. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Inducible Mad2 transgenic mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Mad2-induced instability promotes diverse tumors but 12 imaged tumors continue growing after Mad2 withdrawal.", "what_it_does_not_show": "Forced expression and long latency; withdrawing the inducer does not prove all residual instability disappears.", "confounders_present": [ "Forced expression and long latency; withdrawing the inducer does not prove all residual instability disappears." ], "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": [ "Inducible Mad2 model family reused in Kras recurrence study." ] }, { "n": 38, "pmid": "34266887", "title": "Transient genomic instability drives tumorigenesis through accelerated clonal evolution.", "citation": "Shoshani O, Bakker B, de Haan L et al. Transient genomic instability drives tumorigenesis through accelerated clonal evolution. Genes & development. 2021.", "doi": "10.1101/gad.348319.121", "pmcid": "PMC8336898", "url": "https://pubmed.ncbi.nlm.nih.gov/34266887/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34266887/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34266887", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph2, 0:Results:paragraph3, 0:Results:paragraph4, 0:Results:paragraph5, 0:Results:paragraph7, 0:Results:paragraph9, 0:Results:paragraph17, 0:Results:paragraph18, 0:Results:paragraph20, 0:Results:paragraph24. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Transient Plk4 and p53-stratified mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "A short CIN pulse accelerates thymic lymphoma in p53-deficient contexts and yields selected karyotypes.", "what_it_does_not_show": "Wild-type p53 mice show no survival/tumor increase; ongoing instability is not obligatory once selected states arise.", "confounders_present": [ "Wild-type p53 mice show no survival/tumor increase; ongoing instability is not obligatory once selected states arise." ], "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": "16492765", "title": "53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis.", "citation": "Morales JC, Franco S, Murphy MM et al. 53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis. Proceedings of the National Academy of Sciences of the United States of America. 2006.", "doi": "10.1073/pnas.0511259103", "pmcid": "PMC1413919", "url": "https://pubmed.ncbi.nlm.nih.gov/16492765/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16492765/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID16492765", "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": "53BP1/p53 compound mutant mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Combined endogenous repair/checkpoint defects accelerate lymphoma with structural and numerical errors.", "what_it_does_not_show": "Genetic interaction with an existing driver; repair and checkpoint effects are coupled.", "confounders_present": [ "Genetic interaction with an existing driver; repair and checkpoint effects are coupled." ], "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": "10951588", "title": "The RAS oncogene induces genomic instability in thyroid PCCL3 cells via the MAPK pathway.", "citation": "Saavedra HI, Knauf JA, Shirokawa JM et al. The RAS oncogene induces genomic instability in thyroid PCCL3 cells via the MAPK pathway. Oncogene. 2000.", "doi": "10.1038/sj.onc.1203723", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10951588/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10951588/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID10951588", "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": "Doxycycline-RAS thyroid cells", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Activated RAS rapidly induces micronuclei through MAPK, with pathway-specific contrasts.", "what_it_does_not_show": "Forced driver in culture; demonstrates upstream causation without assigning the frequency in human cancers.", "confounders_present": [ "Forced driver in culture; demonstrates upstream causation without assigning the frequency in 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": 41, "pmid": "26578792", "title": "Chronic centrosome amplification without tumorigenesis.", "citation": "Vitre B, Holland AJ, Kulukian A et al. Chronic centrosome amplification without tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America. 2015.", "doi": "10.1073/pnas.1519388112", "pmcid": "PMC4655534", "url": "https://pubmed.ncbi.nlm.nih.gov/26578792/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26578792/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26578792", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph39, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph43, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph46, 0:Publisher HTML paragraphs:paragraph48, 0:Publisher HTML paragraphs:paragraph49. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Inducible Plk4 mice with p53 and skin carcinogen contrasts", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Centrosome amplification and increased abnormal mitoses do not add tumors or shorten tumor-free survival in tested contexts.", "what_it_does_not_show": "Exposure design, tissues, p53 surveillance and lethal competing tumors differ from positive Plk4 models.", "confounders_present": [ "Exposure design, tissues, p53 surveillance and lethal competing tumors differ from positive Plk4 models." ], "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": "28132847", "title": "Centrosome Amplification Is Sufficient to Promote Spontaneous Tumorigenesis in Mammals.", "citation": "Levine MS, Bakker B, Boeckx B et al. Centrosome Amplification Is Sufficient to Promote Spontaneous Tumorigenesis in Mammals. Developmental cell. 2017.", "doi": "10.1016/j.devcel.2016.12.022", "pmcid": "PMC5296221", "url": "https://pubmed.ncbi.nlm.nih.gov/28132847/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28132847/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28132847", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph4, 1:RESULTS:paragraph8, 1:RESULTS:paragraph9, 1:RESULTS:paragraph10, 1:RESULTS:paragraph11, 1:RESULTS:paragraph12, 1:RESULTS:paragraph13. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "Inducible modest centrosomal Plk4 mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Chronic or transient induction yields persistent centrosome amplification and spontaneous tumors; ApcMin tumor number rises.", "what_it_does_not_show": "Forced inducible system; tissue expression varies, p53 signaling is partly compromised in tumors and CIN-specific pleiotropy is not entirely excluded.", "confounders_present": [ "Forced inducible system; tissue expression varies, p53 signaling is partly compromised in tumors and CIN-specific pleiotropy is not entirely excluded." ], "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": "18555779", "title": "Centrosome amplification can initiate tumorigenesis in flies.", "citation": "Basto R, Brunk K, Vinadogrova T et al. Centrosome amplification can initiate tumorigenesis in flies. Cell. 2008.", "doi": "10.1016/j.cell.2008.05.039", "pmcid": "PMC2653712", "url": "https://pubmed.ncbi.nlm.nih.gov/18555779/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18555779/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID18555779", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Drosophila neuroblast centrosome amplification", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Extra centrosomes disrupt asymmetric division and generate transplantable tumors despite stable diploid tissue genomes.", "what_it_does_not_show": "Nonmammalian context; argues that centrosome effects can act outside a large CIN pathway.", "confounders_present": [ "Nonmammalian context; argues that centrosome effects can act outside a large CIN pathway." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 44, "pmid": "24739973", "title": "Oncogene-like induction of cellular invasion from centrosome amplification.", "citation": "Godinho SA, Picone R, Burute M et al. Oncogene-like induction of cellular invasion from centrosome amplification. Nature. 2014.", "doi": "10.1038/nature13277", "pmcid": "PMC4061398", "url": "https://pubmed.ncbi.nlm.nih.gov/24739973/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24739973/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24739973", "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": "Human mammary 3D culture", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Centrosome amplification promotes invasion through microtubule/Rac1 changes.", "what_it_does_not_show": "Cytoskeletal effects are distinct from genome-change rates; invasion in culture is not metastasis necessity.", "confounders_present": [ "Cytoskeletal effects are distinct from genome-change rates; invasion in culture is not metastasis 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": 45, "pmid": "39181133", "title": "The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance.", "citation": "Engel JL, Zhang X, Wu M et al. The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance. Cell. 2024.", "doi": "10.1016/j.cell.2024.08.001", "pmcid": "PMC11490392", "url": "https://pubmed.ncbi.nlm.nih.gov/39181133/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39181133/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39181133", "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": "Strong", "system": "Human micronucleus and drug-resistance models", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Noncanonical Fanconi machinery promotes micronuclear fragmentation and ecDNA-associated resistance.", "what_it_does_not_show": "Pathway effects differ between micronuclei and interphase nuclei; treatment-selected cell models.", "confounders_present": [ "Pathway effects differ between micronuclei and interphase nuclei; treatment-selected cell models." ], "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": "39814020", "title": "Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution.", "citation": "Espejo Valle-Inclan J, De Noon S, Trevers K et al. Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution. Cell. 2025.", "doi": "10.1016/j.cell.2024.12.005", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39814020/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39814020/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39814020", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Multi-region human osteosarcoma genomes", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Subclonal chromothripsis and amplification support continuing tumor evolution histories.", "what_it_does_not_show": "Timing is reconstructed from samples rather than prospectively measured or causally corrected initiation.", "confounders_present": [ "Timing is reconstructed from samples rather than prospectively measured or causally corrected 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": 47, "pmid": "33361815", "title": "Chromothripsis drives the evolution of gene amplification in cancer.", "citation": "Shoshani O, Brunner SF, Yaeger R et al. Chromothripsis drives the evolution of gene amplification in cancer. Nature. 2021.", "doi": "10.1038/s41586-020-03064-z", "pmcid": "PMC7933129", "url": "https://pubmed.ncbi.nlm.nih.gov/33361815/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33361815/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID33649505" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33361815", "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": "Strong", "system": "Clonal ecDNA/drug selection experiments", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Chromothripsis generates ecDNA amplification and selectable resistance with DNA-repair perturbations.", "what_it_does_not_show": "Treatment selection and cell models; linked erratum details unexamined.", "confounders_present": [ "Treatment selection and cell models; linked erratum details unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "26017310", "title": "Chromothripsis from DNA damage in micronuclei.", "citation": "Zhang CZ, Spektor A, Cornils H et al. Chromothripsis from DNA damage in micronuclei. Nature. 2015.", "doi": "10.1038/nature14493", "pmcid": "PMC4742237", "url": "https://pubmed.ncbi.nlm.nih.gov/26017310/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26017310/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26017310", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Live imaging and single-cell genome tracking", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Micronuclear replication/segregation can generate chromothripsis within one cell cycle.", "what_it_does_not_show": "Demonstrates process capacity, not a general initiating or maintenance necessity in patients.", "confounders_present": [ "Demonstrates process capacity, not a general initiating or maintenance necessity in patients." ], "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": "17136094", "title": "Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication.", "citation": "Di Micco R, Fumagalli M, Cicalese A et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006.", "doi": "10.1038/nature05327", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17136094/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17136094/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17136094", "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": "Strong", "system": "Oncogenic RAS cell and mouse senescence models", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Oncogene-induced hyperreplication triggers a damage response and senescence barrier.", "what_it_does_not_show": "Abstract-only original; upstream oncogene and barrier removal do not establish universal rates or endogenous initiating order.", "confounders_present": [ "Abstract-only original; upstream oncogene and barrier removal do not establish universal rates or endogenous initiating 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": 50, "pmid": "15829956", "title": "DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis.", "citation": "Bartkova J, Horejsí Z, Koed K et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005.", "doi": "10.1038/nature03482", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15829956/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15829956/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID15829956", "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 early lesions and oncogene cell models", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "DNA-damage signaling appears in early lesions and oncogene-driven models before overt instability.", "what_it_does_not_show": "Cross-sectional human stages are not serial clonal trajectories; checkpoint activity can protect against cancer.", "confounders_present": [ "Cross-sectional human stages are not serial clonal trajectories; checkpoint activity can protect against cancer." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "17136093", "title": "Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.", "citation": "Bartkova J, Rezaei N, Liontos M et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006.", "doi": "10.1038/nature05268", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17136093/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17136093/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17136093", "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": "Strong", "system": "Human lesions and ATM/senescence mouse perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Disabling the damage response relaxes oncogene-induced senescence and increases invasive behavior.", "what_it_does_not_show": "Checkpoint intervention changes survival and selection, not just mutation rate; tissue-specific experimental context.", "confounders_present": [ "Checkpoint intervention changes survival and selection, not just mutation rate; tissue-specific experimental context." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "8674041", "title": "MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis.", "citation": "Reitmair AH, Cai JC, Bjerknes M et al. MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis. Cancer research. 1996.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/8674041/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/8674041/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID8674041", "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": "Msh2-null ApcMin mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Repair deficiency accelerates adenomas and changes routes of Apc inactivation.", "what_it_does_not_show": "Inherited Apc driver already present; not instability-alone initiation or all-cancer necessity.", "confounders_present": [ "Inherited Apc driver already present; not instability-alone initiation or all-cancer 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": 53, "pmid": "9244348", "title": "Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice.", "citation": "Andrew SE, Reitmair AH, Fox J et al. Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice. Oncogene. 1997.", "doi": "10.1038/sj.onc.1201180", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9244348/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9244348/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID9244348", "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": "Msh2-null reporter mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Normal tissues accumulate greater reporter mutation frequencies after endogenous repair loss.", "what_it_does_not_show": "Frequency per sampled tissue is not per-division rate; reporter and tissue selection limit generalization.", "confounders_present": [ "Frequency per sampled tissue is not per-division rate; reporter and tissue selection limit generalization." ], "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": "9973196", "title": "The human MLH1 cDNA complements DNA mismatch repair defects in Mlh1-deficient mouse embryonic fibroblasts.", "citation": "Buermeyer AB, Wilson-Van Patten C, Baker SM et al. The human MLH1 cDNA complements DNA mismatch repair defects in Mlh1-deficient mouse embryonic fibroblasts. Cancer research. 1999.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9973196/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9973196/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID9973196", "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": "MLH1-deficient cell complementation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "MLH1 restoration decreases substitution/microsatellite mutation and restores associated MMR functions.", "what_it_does_not_show": "Repair rescue in cultured cells is not a prevention or regression experiment in tumors.", "confounders_present": [ "Repair rescue in cultured cells is not a prevention or regression experiment 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": 55, "pmid": "7628020", "title": "Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer.", "citation": "de Wind N, Dekker M, Berns A et al. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell. 1995.", "doi": "10.1016/0092-8674(95)90319-4", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/7628020/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/7628020/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID7628020", "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": "Endogenous Msh2-null mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Repair loss establishes a mutator/recombination phenotype and tumor susceptibility.", "what_it_does_not_show": "Predisposition and essential repair changes do not identify instability as the sole immediate transforming lesion.", "confounders_present": [ "Predisposition and essential repair changes do not identify instability as the sole immediate transforming lesion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Msh2 founding line and later longitudinal follow-up." ] }, { "n": 56, "pmid": "8706033", "title": "Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice.", "citation": "Reitmair AH, Redston M, Cai JC et al. Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice. Cancer research. 1996.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/8706033/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/8706033/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID8706033", "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": "Strong", "system": "Msh2-null longitudinal mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Lymphoma and intestinal tumors accrue with endogenous repair loss and Apc inactivation.", "what_it_does_not_show": "Same Msh2 model family as 1995; not independent genetic replication or universal cancer causation.", "confounders_present": [ "Same Msh2 model family as 1995; not independent genetic replication or universal cancer causation." ], "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": [ "Msh2 founding line and later longitudinal follow-up." ] }, { "n": 57, "pmid": "14744753", "title": "Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency.", "citation": "Dai W, Wang Q, Liu T et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer research. 2004.", "doi": "10.1158/0008-5472.can-03-3119", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/14744753/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/14744753/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID14744753", "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": "BubR1-haploinsufficient carcinogen-treated mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Checkpoint defects increase micronuclei and carcinogen-associated adenoma incidence.", "what_it_does_not_show": "Carcinogen context and pleiotropic checkpoint function; spontaneous all-cancer root not tested.", "confounders_present": [ "Carcinogen context and pleiotropic checkpoint function; spontaneous all-cancer root not tested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "23878276", "title": "Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation.", "citation": "Park I, Lee HO, Choi E et al. Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation. The Journal of cell biology. 2013.", "doi": "10.1083/jcb.201210099", "pmcid": "PMC3718975", "url": "https://pubmed.ncbi.nlm.nih.gov/23878276/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23878276/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID23878276", "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": "Endogenous BubR1 K243R mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A domain mutation weakens checkpoint/attachment fidelity and raises spontaneous tumor susceptibility.", "what_it_does_not_show": "Mutant mimics a regulatory defect with multiple consequences and selected cooperating p53 changes.", "confounders_present": [ "Mutant mimics a regulatory defect with multiple consequences and selected cooperating p53 changes." ], "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": "23209306", "title": "Bub1 kinase activity drives error correction and mitotic checkpoint control but not tumor suppression.", "citation": "Ricke RM, Jeganathan KB, Malureanu L et al. Bub1 kinase activity drives error correction and mitotic checkpoint control but not tumor suppression. The Journal of cell biology. 2012.", "doi": "10.1083/jcb.201205115", "pmcid": "PMC3518220", "url": "https://pubmed.ncbi.nlm.nih.gov/23209306/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23209306/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID23209306", "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", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Endogenous kinase-dead Bub1 mice", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "Substantial chromosome errors and aneuploidy occur without increased tumors in tested challenges.", "what_it_does_not_show": "Modular endogenous negative evidence; genotype and measured error types matter, not all instability is tumor promoting.", "confounders_present": [ "Modular endogenous negative evidence; genotype and measured error types matter, not all instability is tumor promoting." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 60, "pmid": "27528194", "title": "BubR1 alterations that reinforce mitotic surveillance act against aneuploidy and cancer.", "citation": "Weaver RL, Limzerwala JF, Naylor RM et al. BubR1 alterations that reinforce mitotic surveillance act against aneuploidy and cancer. eLife. 2016.", "doi": "10.7554/eLife.16620", "pmcid": "PMC4987139", "url": "https://pubmed.ncbi.nlm.nih.gov/27528194/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27528194/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27528194", "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": "BubR1 dosage/domain mouse engineering", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Improving segregation fidelity protects against aneuploidy and cancer in tested contexts.", "what_it_does_not_show": "Domain mechanisms and tissue scope differ from simple checkpoint-strength assumptions.", "confounders_present": [ "Domain mechanisms and tissue scope differ from simple checkpoint-strength assumptions." ], "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": 61, "pmid": "20173739", "title": "Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal.", "citation": "Sotillo R, Schvartzman JM, Socci ND et al. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature. 2010.", "doi": "10.1038/nature08803", "pmcid": "PMC2841716", "url": "https://pubmed.ncbi.nlm.nih.gov/20173739/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20173739/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20173739", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Main text:paragraph0, 3:Main text:paragraph1, 3:Main text:paragraph3, 3:Main text:paragraph5, 3:Main text:paragraph6, 3:Main text:paragraph7, 3:Main text:paragraph8, 3:Main text:paragraph9, 3:Main text:paragraph10. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Kras/Mad2 inducible lung mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Mad2 coexpression increases progression and later recurrence after both transgenes are withdrawn, without blocking initial Kras-dependent regression.", "what_it_does_not_show": "Aneuploid burden at recurrence is not an ongoing measured rate; de novo recurrence cannot be formally excluded and model is forced.", "confounders_present": [ "Aneuploid burden at recurrence is not an ongoing measured rate; de novo recurrence cannot be formally excluded and model is forced." ], "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": [ "Inducible Mad2 model family." ] } ], "verification_summary": { "load_bearing_claims_checked": 66, "verified": 66, "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": "Tumor genomes and direct cell-division assays establish that changing genomes exist; mere occurrence is descriptive under the causal rubric. Burden, frequency and inferred historical process are distinguished from per-division rate.", "resulting_ceiling": "Β" }, { "subclaim_id": "SC4", "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": "Mechanistic and in vivo causal contributions make a broad instability-first model plausible, but no matching evidence establishes general primacy over upstream oncogenes or context-dependent amplification. Negative endogenous models and transient initiation with continued tumor growth distinguish contribution from obligatory ongoing root.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Ongoing genome instability is the primary root cause of cancer initiation and malignant progression rather than a consequence of oncogenic transformation or a context-dependent accelerator.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Whole-case convergence supports Ζ for defined susceptibility and for bounded suppressive barriers; a cell-only cap cannot erase the assembled endogenous evidence. The same sources cannot upgrade the exact general-root gate. Progression is Ε because direct rate and course controls are valid but shared transplant programmes and engineered treatment models limit independent endogenous generalization.", "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": "", "gamma_hard_rules_triggered": [ "Fixed aneuploid states, driver mutations, inferred signatures and mutation frequency are not automatically rates.", "CIN perturbations must retain proliferation, centrosome/cytoskeletal effects and initial tumor burden controls.", "Forced Mad2/Plk4 experiments establish capacity at their exposure and tissue scope, not all sporadic origin.", "Transgene withdrawal does not establish that every remaining instability process is zero.", "Initiation, maintenance, metastasis and treatment escape require different causal endpoints." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Tumor genomes and direct cell-division assays establish that changing genomes exist; mere occurrence is descriptive under the causal rubric. Burden, frequency and inferred historical process are distinguished from per-division rate.", "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": "yes", "qualifying_evidence_citation": "PMID23187126, PMID21383776, PMID11376699, PMID11861370, PMID9244348, PMID9973196, PMID7628020, PMID23878276, PMID27528194", "gamma_hard_rules_triggered": [ "Fixed aneuploid states, driver mutations, inferred signatures and mutation frequency are not automatically rates.", "CIN perturbations must retain proliferation, centrosome/cytoskeletal effects and initial tumor burden controls.", "Forced Mad2/Plk4 experiments establish capacity at their exposure and tissue scope, not all sporadic origin.", "Transgene withdrawal does not establish that every remaining instability process is zero.", "Initiation, maintenance, metastasis and treatment escape require different causal endpoints." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Endogenous MMR, repair-domain and segregation-gene models, normal-tissue mutator measurements and cell repair complementation converge on defined susceptibility. Gene pleiotropy, cooperating drivers and tissue-specific negative outcomes bound the conclusion; susceptibility is not immediate sole transformation.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID37612508, PMID29342134, PMID34352222, PMID38871738, PMID32030896, PMID35905505, PMID20173739", "gamma_hard_rules_triggered": [ "Fixed aneuploid states, driver mutations, inferred signatures and mutation frequency are not automatically rates.", "CIN perturbations must retain proliferation, centrosome/cytoskeletal effects and initial tumor burden controls.", "Forced Mad2/Plk4 experiments establish capacity at their exposure and tissue scope, not all sporadic origin.", "Transgene withdrawal does not establish that every remaining instability process is zero.", "Initiation, maintenance, metastasis and treatment escape require different causal endpoints." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Measured rate correction changes metastasis independently of karyotypic burden, and CIN manipulations alter resistance and recurrence in specified oncogene/treatment models. Most interventions are engineered or transplant based; host dependence, shared programmes and lack of matched independent autochthonous rate-restoration course tests prevent a field-wide upper grade.", "ceiling_from_boundary_check": "Δ or higher" }, { "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": "", "gamma_hard_rules_triggered": [ "Fixed aneuploid states, driver mutations, inferred signatures and mutation frequency are not automatically rates.", "CIN perturbations must retain proliferation, centrosome/cytoskeletal effects and initial tumor burden controls.", "Forced Mad2/Plk4 experiments establish capacity at their exposure and tissue scope, not all sporadic origin.", "Transgene withdrawal does not establish that every remaining instability process is zero.", "Initiation, maintenance, metastasis and treatment escape require different causal endpoints." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Mechanistic and in vivo causal contributions make a broad instability-first model plausible, but no matching evidence establishes general primacy over upstream oncogenes or context-dependent amplification. Negative endogenous models and transient initiation with continued tumor growth distinguish contribution from obligatory ongoing root.", "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": [], "what_would_cross_it": "Separate description from causality: measure a predefined endogenous rate before transformation and show that selective rate correction changes a cancer endpoint." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[8] USP44 loss causes segregation defects and spontaneous lung tumors; centrin interaction separates centrosome positioning from checkpoint delay.", "[26] Defective PCNA interaction compromises replication/repair and increases instability, transformation and tumors.", "[35] Endogenous Brca1 loss predisposes mammary tumors with later cooperating alterations.", "[36] Viable homozygous domain-mutant animals develop more tumors and shorter survival.", "[53] Normal tissues accumulate greater reporter mutation frequencies after endogenous repair loss.", "[54] MLH1 restoration decreases substitution/microsatellite mutation and restores associated MMR functions.", "[55] Repair loss establishes a mutator/recombination phenotype and tumor susceptibility.", "[58] A domain mutation weakens checkpoint/attachment fidelity and raises spontaneous tumor susceptibility.", "[60] Improving segregation fidelity protects against aneuploidy and cancer in tested contexts." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[8] USP44 loss causes segregation defects and spontaneous lung tumors; centrin interaction separates centrosome positioning from checkpoint delay.", "[26] Defective PCNA interaction compromises replication/repair and increases instability, transformation and tumors.", "[35] Endogenous Brca1 loss predisposes mammary tumors with later cooperating alterations.", "[36] Viable homozygous domain-mutant animals develop more tumors and shorter survival.", "[53] Normal tissues accumulate greater reporter mutation frequencies after endogenous repair loss.", "[54] MLH1 restoration decreases substitution/microsatellite mutation and restores associated MMR functions.", "[55] Repair loss establishes a mutator/recombination phenotype and tumor susceptibility.", "[58] A domain mutation weakens checkpoint/attachment fidelity and raises spontaneous tumor susceptibility.", "[60] Improving segregation fidelity protects against aneuploidy and cancer in tested contexts." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "yes", "supporting_evidence": [ "[8] USP44 loss causes segregation defects and spontaneous lung tumors; centrin interaction separates centrosome positioning from checkpoint delay.", "[26] Defective PCNA interaction compromises replication/repair and increases instability, transformation and tumors.", "[35] Endogenous Brca1 loss predisposes mammary tumors with later cooperating alterations.", "[36] Viable homozygous domain-mutant animals develop more tumors and shorter survival.", "[53] Normal tissues accumulate greater reporter mutation frequencies after endogenous repair loss.", "[54] MLH1 restoration decreases substitution/microsatellite mutation and restores associated MMR functions.", "[55] Repair loss establishes a mutator/recombination phenotype and tumor susceptibility.", "[58] A domain mutation weakens checkpoint/attachment fidelity and raises spontaneous tumor susceptibility.", "[60] Improving segregation fidelity protects against aneuploidy and cancer in tested contexts." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Η", "requirement_quoted": "Requires:\n- Strong endogenous evidence\n- Therapeutic or mechanistic consequence\n- Reproducibility across disease settings within the claimed scope", "satisfied": "no", "supporting_evidence": [ "[8] USP44 loss causes segregation defects and spontaneous lung tumors; centrin interaction separates centrosome positioning from checkpoint delay.", "[26] Defective PCNA interaction compromises replication/repair and increases instability, transformation and tumors.", "[35] Endogenous Brca1 loss predisposes mammary tumors with later cooperating alterations.", "[36] Viable homozygous domain-mutant animals develop more tumors and shorter survival.", "[53] Normal tissues accumulate greater reporter mutation frequencies after endogenous repair loss.", "[54] MLH1 restoration decreases substitution/microsatellite mutation and restores associated MMR functions.", "[55] Repair loss establishes a mutator/recombination phenotype and tumor susceptibility.", "[58] A domain mutation weakens checkpoint/attachment fidelity and raises spontaneous tumor susceptibility.", "[60] Improving segregation fidelity protects against aneuploidy and cancer in tested contexts." ], "what_would_cross_it": "Complete genotype-matched repair/segregation restoration in independent spontaneous lineages with directly measured rates and initiation endpoints; separate pleiotropic functions." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[1] CIN rate and cGAS-STING/ER-stress perturbations alter metastasis through host immune context.", "[2] KIF2B/MCAK lower measured missegregation without normalizing aneuploid burden; metastasis falls and Mad2 partially restores it.", "[13] Transient CIN generates recurrent aneuploid resistant clones; a specified chromosome loss confers paclitaxel resistance.", "[15] Whole-genome doubling and copy-number routes alter targeted-treatment responses.", "[18] CIN promotes escape through MET amplification and creates a new cMet dependency.", "[19] Reducing CIN changes resistance timing and copy-number routes without changing initial xenograft growth.", "[61] Mad2 coexpression increases progression and later recurrence after both transgenes are withdrawn, without blocking initial Kras-dependent regression." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[1] CIN rate and cGAS-STING/ER-stress perturbations alter metastasis through host immune context.", "[2] KIF2B/MCAK lower measured missegregation without normalizing aneuploid burden; metastasis falls and Mad2 partially restores it.", "[13] Transient CIN generates recurrent aneuploid resistant clones; a specified chromosome loss confers paclitaxel resistance.", "[15] Whole-genome doubling and copy-number routes alter targeted-treatment responses.", "[18] CIN promotes escape through MET amplification and creates a new cMet dependency.", "[19] Reducing CIN changes resistance timing and copy-number routes without changing initial xenograft growth.", "[61] Mad2 coexpression increases progression and later recurrence after both transgenes are withdrawn, without blocking initial Kras-dependent regression." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "no", "supporting_evidence": [ "[1] CIN rate and cGAS-STING/ER-stress perturbations alter metastasis through host immune context.", "[2] KIF2B/MCAK lower measured missegregation without normalizing aneuploid burden; metastasis falls and Mad2 partially restores it.", "[13] Transient CIN generates recurrent aneuploid resistant clones; a specified chromosome loss confers paclitaxel resistance.", "[15] Whole-genome doubling and copy-number routes alter targeted-treatment responses.", "[18] CIN promotes escape through MET amplification and creates a new cMet dependency.", "[19] Reducing CIN changes resistance timing and copy-number routes without changing initial xenograft growth.", "[61] Mad2 coexpression increases progression and later recurrence after both transgenes are withdrawn, without blocking initial Kras-dependent regression." ], "what_would_cross_it": "Replicate independent post-onset rate restoration in autochthonous tumors with clonal tracking, preserved driver signaling and host-immune controls." }, { "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": [], "what_would_cross_it": "Prospectively compare instability-first with driver-first trajectories across predefined sporadic tissues and selectively normalize rates before initiation, preserving other gene functions, followed by rescue/reinstatement." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "KIF2A depolymerizing control, unchanged proliferation/centrosome counts, persistent aneuploidy and Mad2 re-elevation distinguish rate in metastasis models (PMID29342134).", "Sting/Cgas genetic contrasts and BALB/c versus NSG hosts distinguish tumor and host contributions (PMID37612508).", "Ink4a and MLH1 tumor contexts show added CIN without added cancer course (PMID24133140).", "p53 wild-type, heterozygous and null strata respond differently to the same transient CIN induction (PMID34266887).", "Kinase-dead Bub1 causes errors without added tumors (PMID23209306).", "Mad2 withdrawal and Kras withdrawal separate maintenance of the inducer from driver dependence (PMID17189715,20173739)." ], "note": "Prespecified cancer lineages, stages, immune hosts, p53 status and error classes are boundaries. MMR mutation burden, whole-chromosome rates and ecDNA/chromothripsis are not pooled as one interchangeable exposure. Cross-sectional tumor genomes cannot identify the initiating root, and constitutional susceptibility does not establish every sporadic trajectory." }, "falsification_patterns_met": [ { "pattern": "Disease occurs without the claimed obligatory feature", "evidence": "Mad2-induced tumors continue growing after Mad2 induction is withdrawn, and a transient CIN pulse can precede tumors; neither experiment proves every residual error process is absent (PMID17189715,34266887).", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "State substituted for rate", "where": "Fixed chromosome addiction, copy-number signatures and reporter mutation frequency receive separate limitations." }, { "pitfall": "Initiation conflated with later selection", "where": "Metastasis, drug resistance and Kras recurrence never become all-cancer initiation evidence." }, { "pitfall": "Perturbation pleiotropy ignored", "where": "Centrosome invasion, p53 signaling, BRCA and checkpoint gene functions are separated where possible." }, { "pitfall": "Negative evidence ignored", "where": "Bub1, p53-wild-type transient CIN, Ink4a/MLH1 and Vitre contrasts are retained." }, { "pitfall": "Provider output promoted to original evidence", "where": "Review-heavy timeline and gap matrix are discovery only; three named claims are compared with originals." } ], "causal_tally_audit": { "tally_claimed_by_document": 34, "tally_after_audit": 34, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Positive susceptibility sources cannot be tallied as positive evidence for general primacy.", "Negative or null contrasts do not inflate positive-support counts." ] }, "steelman": { "case_one_rung_higher": "One rung higher Δ: endogenous mutator and segregation models demonstrate that instability-related mechanisms can materially initiate cancer susceptibility.", "case_one_rung_lower": "One rung lower Β: genome abnormalities are merely correlates. That ignores causal genetics, functional repair complementation and rate-specific course changes.", "which_rejected": "The nominal mechanism exceeds association, so Β is too low. Δ would require evidence matching its general-root primacy, not transfer from selected susceptibility or progression cases. Preserve Γ for SC4 and higher narrow grades.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Across prospectively defined sporadic tissues, trace native clones before transformation while measuring division-level mutation/segregation rates and driver activation. Selectively normalize the relevant rate without removing fixed drivers or changing p53, proliferation or centrosome signaling; reinstate the rate and repeat in independent autochthonous models." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "61 primary reports; evidence density, heterogeneous controls and the predominance of engineered and transplant models set the confidence, not correctness and not reviewer access depth.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered general-root gate SC4 remains Γ. Endogenous repair and segregation perturbations establish defined cancer-susceptibility routes (SC2 Ζ), and rate-specific progression or resistance interventions support context-valid causality (SC3 Ε). Associations and fixed abnormal states cannot establish the temporal root of all cancer." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Supported ongoing instability supplies diversity and feedback that can sustain progression or escape. Defined inherited mutator defects can confer initiating susceptibility, but neither that narrower etiological role nor all-context necessity is assigned to the general root claim.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Examined 2025 ovarian genome/imaging and 2025 live division-to-genome studies improve temporal/rate resolution; no future outcome is presumed (PMID 40670783, 41162705). Both are completed publications rather than work being run, and neither addresses the general-primacy boundary check.", "justification": "Examined 2025 ovarian genome/imaging and 2025 live division-to-genome studies improve temporal/rate resolution; no future outcome is presumed (PMID 40670783, 41162705). Both are completed publications rather than work being run, and neither addresses the general-primacy boundary check, so 'Decisive work underway' is not available; corrected on adversarial review 2026-10-14." }, "stability": { "value": "Stable", "trigger": "No specific pending result is claimed to move the general-root grade imminently.", "justification": "No specific pending result is claimed to move the general-root grade 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": "Across prospectively defined sporadic tissues, trace native clones before transformation while measuring division-level mutation/segregation rates and driver activation. Selectively normalize the relevant rate without removing fixed drivers or changing p53, proliferation or centrosome signaling; reinstate the rate and repeat in independent autochthonous models.", "readout": "Clonal initiation hazard, driver timing, measured rates, tumor latency, primary growth, metastasis and treatment-free trajectory", "critical_control": "Driver-matched rate-stable controls, equal proliferation, host immune strata, abundance-matched allele restoration, negative lineages and blinded serial tracking", "supporting_result": "Selective rate normalization prevents initiation across predefined settings and rate reinstatement restores it before driver acquisition; post-onset dependence is separately demonstrated", "falsifying_result": "Initiation proceeds with normalized rates or instability consistently follows driver activation; only resistance or metastasis changes in restricted contexts" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Measure native pre-transformation rates rather than infer them from burden.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Separate repair and checkpoint pleiotropy using modular allele restoration.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Reconcile positive and negative Plk4 models with matched timing, tissue dosage and p53 surveillance.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Trace residual clones in CIN-associated recurrence to exclude de novo tumors.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Independently replicate post-onset rate correction in autochthonous disease.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Separate tumor-intrinsic and host cGAS-STING responses over time.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Map mutation-class-specific promotion/suppression thresholds prospectively.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Distinguish fixed aneuploid-state dependency from continual-rate dependency.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 9", "statement": "Follow normal inherited-mutator tissues longitudinally to the immediate transforming event.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 10", "statement": "Audit linked errata, supplements and inaccessible bodies before complete-paper publication claims.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-08", "reviewer": "Codex", "evidence_base_note": "61 primary reports; literature cutoff 2026-10-08; source examination UTC date 2026-10-09; 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 repair/segregation genetics, normal-tissue longitudinal mutation measurements, selective repair restoration, clonal tracking and prophylactic or therapeutic tumor-course rescue are valid upper-ladder routes. No RCT-only requirement is imposed. Current successes establish scoped pathways, not universal primacy." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Endogenous repair/segregation genetics, normal-tissue longitudinal mutation measurements, selective repair restoration, clonal tracking and prophylactic or therapeutic tumor-course rescue are valid upper-ladder routes. No RCT-only requirement is imposed. Current successes establish scoped pathways, not universal primacy." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Endogenous repair/segregation genetics, normal-tissue longitudinal mutation measurements, selective repair restoration, clonal tracking and prophylactic or therapeutic tumor-course rescue are valid upper-ladder routes. No RCT-only requirement is imposed. Current successes establish scoped pathways, not universal primacy." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Endogenous repair/segregation genetics, normal-tissue longitudinal mutation measurements, selective repair restoration, clonal tracking and prophylactic or therapeutic tumor-course rescue are valid upper-ladder routes. No RCT-only requirement is imposed. Current successes establish scoped pathways, not universal primacy." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Endogenous repair/segregation genetics, normal-tissue longitudinal mutation measurements, selective repair restoration, clonal tracking and prophylactic or therapeutic tumor-course rescue are valid upper-ladder routes. No RCT-only requirement is imposed. Current successes establish scoped pathways, not universal primacy." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 61, "claims_total": 66, "claims_verified": 66, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 61, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "CIN rate and cGAS-STING/ER-stress perturbations alter metastasis through host immune context. Same Bakhoum programme as 2018; engineered transplant models establish progression not all-cancer initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Immune dependence of CIN-driven metastasis, 6:STING inhibitors suppress metastasis. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C2", "text": "KIF2B/MCAK lower measured missegregation without normalizing aneuploid burden; metastasis falls and Mad2 partially restores it. Primary growth does not consistently fall; forced rate correction and transplantation do not establish universal endogenous initiation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:CIN is a driver of metastasis, 3:CIN generates cytosolic DNA, 4:Metastasis from cytosolic DNA response. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C3", "text": "ENPP1 loss and host STING epistasis link extracellular cGAMP handling to metastasis and immune recruitment. Downstream immune mechanism rather than proof that CIN initiates cancer; shared programme.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C4", "text": "Phased copy-number evolution supports ongoing and parallel alteration histories. Historical inference from sampled genomes is not directly measured per-division missegregation or initiating perturbation; cohort overlap.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C5", "text": "Whole-genome-doubling trajectories and imaging reveal heterogeneous ongoing instability states. Selected human tumors; temporal reconstruction and immune-state associations do not establish initiating primacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C6", "text": "High chromosome missegregation suppresses later progression while permitting initiating organoids. Rate and stage dependent; shared CENP-E programme, not evidence against every low-rate contribution.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C7", "text": "Combined high missegregation raises cell death and reduces tumors; extra CENP-E-dependent CIN has no tumor effect in Ink4a or MLH1 contexts. Genetic background, rate and tissue matter; this discriminating negative does not enter a positive-support tally.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph31, 0:Publisher HTML paragraphs:paragraph32, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph35, 0:Publisher HTML paragraphs:paragraph36, 0:Publisher HTML paragraphs:paragraph37, 0:Publisher HTML paragraphs:paragraph38, 0:Publisher HTML paragraphs:paragraph40, 0:Publisher HTML paragraphs:paragraph50. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C8", "text": "USP44 loss causes segregation defects and spontaneous lung tumors; centrin interaction separates centrosome positioning from checkpoint delay. USP44 has multiple functions; endogenous model supports a defined initiating route, not a general root.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C9", "text": "APC mutation subgroups associate with aneuploid burden. Overall APC relationship is weak; cross-sectional burden is not a rate measurement or a causal intervention.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C10", "text": "BubR1 insufficiency increases chromosome errors and colon tumor incidence and grade with an Apc driver. Genetic interaction and checkpoint functions are coupled; no claim that instability alone initiates all cancers.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C11", "text": "Copy-number signatures distinguish putative processes across thousands of tumors. Static patterns and inferred etiologies do not directly measure rates, precedence or necessity.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C12", "text": "cGAS-STING/autophagy removes crisis cells; suppressing the barrier permits unstable proliferating cells. Cell culture and telomere manipulation; linked erratum details unexamined; supports a barrier, not universal tumor suppression.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C13", "text": "Transient CIN generates recurrent aneuploid resistant clones; a specified chromosome loss confers paclitaxel resistance. Fixed resistant state is distinct from continued rate dependence; selected treatment context.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-09", "note": "" }, { "id": "C14", "text": "p53 loss precedes induced CIN, with BRCA1 and MYC adding instability. Nontransformed cultures rather than autochthonous initiation; demonstrates a plausible upstream-driver direction.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C15", "text": "Whole-genome doubling and copy-number routes alter targeted-treatment responses. Treatment-selected evolution and existing drivers; not untreated initiating primacy.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-09", "note": "" }, { "id": "C16", "text": "Direct division-to-genome measurements identify new abnormalities and increased rates with TP53 defects. Near-diploid cultured cells; downstream driver perturbation rather than human initiation.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C17", "text": "RanGAP1 dysregulation couples mitotic disruption, chromothripsis, Rb1 disruption and rapid osteosarcoma. Protein transport, p53 degradation and segregation are coupled; the initiating mechanism is not isolated instability alone.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C18", "text": "CIN promotes escape through MET amplification and creates a new cMet dependency. Established oncogene-driven and withdrawal-selected disease; not original initiation.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-09", "note": "" }, { "id": "C19", "text": "Reducing CIN changes resistance timing and copy-number routes without changing initial xenograft growth. Resistance-specific engineered models; transplant growth alone cannot establish endogenous initiating necessity.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-09", "note": "" }, { "id": "C20", "text": "Chromosome-content changes accompany EMT/reversion with ZEB1 functional interventions. State-selection experiments and transcriptional effects do not isolate ongoing CIN as the sole driver.", "carries_number": true, "load_bearing_for": [ "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": "2026-10-09", "note": "" }, { "id": "C21", "text": "RAS/MAPK activation produces micronuclei, reversed by MEK-pathway inhibition. Forced expression and cultured cells; upstream oncogene can cause instability but this does not quantify all sporadic tumors.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C22", "text": "Removing recurrent trisomy 1q impairs malignant growth through an MDM4-p53 axis. Dependency on a fixed chromosome state is not dependence on the rate of genome change.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C23", "text": "STAG2 loss can affect tumor suppression without aneuploidy or increased aneuploidy after knockdown. Gene pleiotropy and cancer lineage; repair/segregation gene lesions cannot automatically be assigned to CIN.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C24", "text": "Specified trisomies impair proliferation and alter metabolism. Static chromosome states and cultured cells; does not negate every adaptive aneuploidy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C25", "text": "Aneuploidy and CIN impair regenerative fitness in vivo. Regeneration/transplant challenge is not spontaneous tumor initiation; tissue selection boundary.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C26", "text": "Defective PCNA interaction compromises replication/repair and increases instability, transformation and tumors. Repair, replication and checkpoint functions change together; cell-level Chk1 inhibition is not whole-animal repair restoration.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C27", "text": "Defined tissues show spontaneous tumor promotion while other contexts show suppression. Abstract-only; tissue-specific opposing outcomes and shared CENP-E model family limit generalization.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "2026-10-09", "note": "" }, { "id": "C28", "text": "Transcriptional rescue fails to normalize replication stress and S-phase defects. Cultured cells and cohesin pleiotropy; separates transcription from replication, not general initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "2026-10-09", "note": "" }, { "id": "C29", "text": "Oncogenic signaling induces replication stress/APOBEC activity, reduced by RTK inhibition or nucleosides. Enzyme activity is not a measured longitudinal mutation rate or organismal tumor-course rescue.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C30", "text": "Increased fork stress and checkpoint apoptosis reduce polyps and improve survival. Existing Apc driver and repair-protein pleiotropy; excess instability/stress may suppress rather than initiate.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C31", "text": "Exo1-dependent hyperexcision links MMR loss to cytosolic DNA and STING. Repair loss can trigger opposing immune consequences; not a universal tumor-promoting root.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C32", "text": "Increasing the dMMR fraction allows immune rejection in a defined mixture and treatment setting. Mixture threshold and immune context; does not imply prevention of all MMR-deficient tumors.", "carries_number": false, "load_bearing_for": [ "SC3", "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": "2026-10-09", "note": "" }, { "id": "C33", "text": "cGAS/STING governs priming and checkpoint response in repair-defective tumors. Downstream immune context and pre-established tumors; greater instability can favor host control.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C34", "text": "MLH1 manipulation changes resistant mutation frequencies and growth-factor/drug dependence. Cell restoration plus patient association do not establish prospective human tumor prevention.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C35", "text": "Endogenous Brca1 loss predisposes mammary tumors with later cooperating alterations. Long latency and p53 mutations; essential repair, growth and apoptosis functions cannot be reduced to one rate.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C36", "text": "Viable homozygous domain-mutant animals develop more tumors and shorter survival. Domain perturbation has coupled functions; no genotype-matched full repair restoration establishes all-cancer primacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C37", "text": "Mad2-induced instability promotes diverse tumors but 12 imaged tumors continue growing after Mad2 withdrawal. Forced expression and long latency; withdrawing the inducer does not prove all residual instability disappears.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph15, 0:Publisher HTML paragraphs:paragraph22, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph27, 0:Publisher HTML paragraphs:paragraph29, 0:Publisher HTML paragraphs:paragraph30. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C38", "text": "A short CIN pulse accelerates thymic lymphoma in p53-deficient contexts and yields selected karyotypes. Wild-type p53 mice show no survival/tumor increase; ongoing instability is not obligatory once selected states arise.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph2, 0:Results:paragraph3, 0:Results:paragraph4, 0:Results:paragraph5, 0:Results:paragraph7, 0:Results:paragraph9, 0:Results:paragraph17, 0:Results:paragraph18, 0:Results:paragraph20, 0:Results:paragraph24. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C39", "text": "Combined endogenous repair/checkpoint defects accelerate lymphoma with structural and numerical errors. Genetic interaction with an existing driver; repair and checkpoint effects are coupled.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C40", "text": "Activated RAS rapidly induces micronuclei through MAPK, with pathway-specific contrasts. Forced driver in culture; demonstrates upstream causation without assigning the frequency in human cancers.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C41", "text": "Centrosome amplification and increased abnormal mitoses do not add tumors or shorten tumor-free survival in tested contexts. Exposure design, tissues, p53 surveillance and lethal competing tumors differ from positive Plk4 models.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph39, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph43, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph46, 0:Publisher HTML paragraphs:paragraph48, 0:Publisher HTML paragraphs:paragraph49. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C42", "text": "Chronic or transient induction yields persistent centrosome amplification and spontaneous tumors; ApcMin tumor number rises. Forced inducible system; tissue expression varies, p53 signaling is partly compromised in tumors and CIN-specific pleiotropy is not entirely excluded.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph4, 1:RESULTS:paragraph8, 1:RESULTS:paragraph9, 1:RESULTS:paragraph10, 1:RESULTS:paragraph11, 1:RESULTS:paragraph12, 1:RESULTS:paragraph13. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C43", "text": "Extra centrosomes disrupt asymmetric division and generate transplantable tumors despite stable diploid tissue genomes. Nonmammalian context; argues that centrosome effects can act outside a large CIN pathway.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C44", "text": "Centrosome amplification promotes invasion through microtubule/Rac1 changes. Cytoskeletal effects are distinct from genome-change rates; invasion in culture is not metastasis necessity.", "carries_number": true, "load_bearing_for": [ "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": "2026-10-09", "note": "" }, { "id": "C45", "text": "Noncanonical Fanconi machinery promotes micronuclear fragmentation and ecDNA-associated resistance. Pathway effects differ between micronuclei and interphase nuclei; treatment-selected cell models.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C46", "text": "Subclonal chromothripsis and amplification support continuing tumor evolution histories. Timing is reconstructed from samples rather than prospectively measured or causally corrected initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C47", "text": "Chromothripsis generates ecDNA amplification and selectable resistance with DNA-repair perturbations. Treatment selection and cell models; linked erratum details unexamined.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C48", "text": "Micronuclear replication/segregation can generate chromothripsis within one cell cycle. Demonstrates process capacity, not a general initiating or maintenance necessity in patients.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C49", "text": "Oncogene-induced hyperreplication triggers a damage response and senescence barrier. Abstract-only original; upstream oncogene and barrier removal do not establish universal rates or endogenous initiating order.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C50", "text": "DNA-damage signaling appears in early lesions and oncogene-driven models before overt instability. Cross-sectional human stages are not serial clonal trajectories; checkpoint activity can protect against cancer.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C51", "text": "Disabling the damage response relaxes oncogene-induced senescence and increases invasive behavior. Checkpoint intervention changes survival and selection, not just mutation rate; tissue-specific experimental context.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C52", "text": "Repair deficiency accelerates adenomas and changes routes of Apc inactivation. Inherited Apc driver already present; not instability-alone initiation or all-cancer necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C53", "text": "Normal tissues accumulate greater reporter mutation frequencies after endogenous repair loss. Frequency per sampled tissue is not per-division rate; reporter and tissue selection limit generalization.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C54", "text": "MLH1 restoration decreases substitution/microsatellite mutation and restores associated MMR functions. Repair rescue in cultured cells is not a prevention or regression experiment in tumors.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C55", "text": "Repair loss establishes a mutator/recombination phenotype and tumor susceptibility. Predisposition and essential repair changes do not identify instability as the sole immediate transforming lesion.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C56", "text": "Lymphoma and intestinal tumors accrue with endogenous repair loss and Apc inactivation. Same Msh2 model family as 1995; not independent genetic replication or universal cancer causation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C57", "text": "Checkpoint defects increase micronuclei and carcinogen-associated adenoma incidence. Carcinogen context and pleiotropic checkpoint function; spontaneous all-cancer root not tested.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C58", "text": "A domain mutation weakens checkpoint/attachment fidelity and raises spontaneous tumor susceptibility. Mutant mimics a regulatory defect with multiple consequences and selected cooperating p53 changes.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C59", "text": "Substantial chromosome errors and aneuploidy occur without increased tumors in tested challenges. Modular endogenous negative evidence; genotype and measured error types matter, not all instability is tumor promoting.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "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": "2026-10-09", "note": "" }, { "id": "C60", "text": "Improving segregation fidelity protects against aneuploidy and cancer in tested contexts. Domain mechanisms and tissue scope differ from simple checkpoint-strength assumptions.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C61", "text": "Mad2 coexpression increases progression and later recurrence after both transgenes are withdrawn, without blocking initial Kras-dependent regression. Aneuploid burden at recurrence is not an ongoing measured rate; de novo recurrence cannot be formally excluded and model is forced.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Main text:paragraph0, 3:Main text:paragraph1, 3:Main text:paragraph3, 3:Main text:paragraph5, 3:Main text:paragraph6, 3:Main text:paragraph7, 3:Main text:paragraph8, 3:Main text:paragraph9, 3:Main text:paragraph10. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC1", "text": "Tumor genomes and direct cell-division assays establish that changing genomes exist; mere occurrence is descriptive under the causal rubric. Burden, frequency and inferred historical process are distinguished from per-division rate.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 4, 5, 8, 9, 10, 11, 14, 16, 17, 21, 24, 26, 28, 29, 35, 36, 37, 38, 39, 40, 42, 46, 48, 49, 50, 51, 52, 53, 54, 55, 57, 58, 59, 60, 61 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC2", "text": "Endogenous MMR, repair-domain and segregation-gene models, normal-tissue mutator measurements and cell repair complementation converge on defined susceptibility. Gene pleiotropy, cooperating drivers and tissue-specific negative outcomes bound the conclusion; susceptibility is not immediate sole transformation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 6, 7, 8, 9, 10, 12, 14, 17, 23, 25, 26, 27, 30, 31, 35, 36, 37, 38, 39, 41, 42, 43, 52, 53, 54, 55, 56, 57, 58, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC3", "text": "Measured rate correction changes metastasis independently of karyotypic burden, and CIN manipulations alter resistance and recurrence in specified oncogene/treatment models. Most interventions are engineered or transplant based; host dependence, shared programmes and lack of matched independent autochthonous rate-restoration course tests prevent a field-wide upper grade.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 13, 15, 18, 19, 20, 22, 31, 32, 33, 34, 37, 38, 44, 45, 46, 47, 48, 61 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC4", "text": "Mechanistic and in vivo causal contributions make a broad instability-first model plausible, but no matching evidence establishes general primacy over upstream oncogenes or context-dependent amplification. Negative endogenous models and transient initiation with continued tumor growth distinguish contribution from obligatory ongoing root.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 6, 7, 12, 14, 21, 23, 24, 25, 27, 28, 29, 30, 32, 37, 38, 40, 41, 43, 49, 50, 51, 59, 61 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CH", "text": "Genome instability can cause susceptibility and accelerate selected cancers; its general initiating primacy is unproved.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 55, 8, 2, 7, 38, 61 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-09", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Li J, Hubisz MJ, Earlie EM et al. Non-cell-autonomous cancer progression from chromosomal instability. Nature. 2023.", "tier": "A", "kind": "primary", "pmid": "37612508", "doi": "10.1038/s41586-023-06464-z", "url": "https://pubmed.ncbi.nlm.nih.gov/37612508/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37612508", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Immune dependence of CIN-driven metastasis, 6:STING inhibitors suppress metastasis. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC3" ] }, { "n": 2, "citation": "Bakhoum SF, Ngo B, Laughney AM et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018.", "tier": "A", "kind": "primary", "pmid": "29342134", "doi": "10.1038/nature25432", "url": "https://pubmed.ncbi.nlm.nih.gov/29342134/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29342134", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:CIN is a driver of metastasis, 3:CIN generates cytosolic DNA, 4:Metastasis from cytosolic DNA response. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC3", "CH" ] }, { "n": 3, "citation": "Li J, Duran MA, Dhanota N et al. Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis. Cancer discovery. 2021.", "tier": "A", "kind": "primary", "pmid": "33372007", "doi": "10.1158/2159-8290.CD-20-0387", "url": "https://pubmed.ncbi.nlm.nih.gov/33372007/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33372007", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC3" ] }, { "n": 4, "citation": "Watkins TBK, Lim EL, Petkovic M et al. Pervasive chromosomal instability and karyotype order in tumour evolution. Nature. 2020.", "tier": "A", "kind": "primary", "pmid": "32879494", "doi": "10.1038/s41586-020-2698-6", "url": "https://pubmed.ncbi.nlm.nih.gov/32879494/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32879494", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC1", "CSC3" ] }, { "n": 5, "citation": "McPherson A, Vázquez-García I, Myers MA et al. Ongoing genome doubling shapes evolvability and immunity in ovarian cancer. Nature. 2025.", "tier": "A", "kind": "primary", "pmid": "40670783", "doi": "10.1038/s41586-025-09240-3", "url": "https://pubmed.ncbi.nlm.nih.gov/40670783/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40670783", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC1", "CSC3" ] }, { "n": 6, "citation": "Zasadil LM, Britigan EM, Ryan SD et al. High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation. Molecular biology of the cell. 2016.", "tier": "A", "kind": "primary", "pmid": "27146113", "doi": "10.1091/mbc.E15-10-0747", "url": "https://pubmed.ncbi.nlm.nih.gov/27146113/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27146113", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC2", "CSC3", "CSC4" ] }, { "n": 7, "citation": "Silk AD, Zasadil LM, Holland AJ et al. Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors. Proceedings of the National Academy of Sciences of the United States of America. 2013.", "tier": "A", "kind": "primary", "pmid": "24133140", "doi": "10.1073/pnas.1317042110", "url": "https://pubmed.ncbi.nlm.nih.gov/24133140/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24133140", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph31, 0:Publisher HTML paragraphs:paragraph32, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph35, 0:Publisher HTML paragraphs:paragraph36, 0:Publisher HTML paragraphs:paragraph37, 0:Publisher HTML paragraphs:paragraph38, 0:Publisher HTML paragraphs:paragraph40, 0:Publisher HTML paragraphs:paragraph50. 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Nature. 2006.", "tier": "A", "kind": "primary", "pmid": "17136093", "doi": "10.1038/nature05268", "url": "https://pubmed.ncbi.nlm.nih.gov/17136093/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17136093", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C51", "CSC1", "CSC4" ] }, { "n": 52, "citation": "Reitmair AH, Cai JC, Bjerknes M et al. MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis. 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BubR1 alterations that reinforce mitotic surveillance act against aneuploidy and cancer. eLife. 2016.", "tier": "A", "kind": "primary", "pmid": "27528194", "doi": "10.7554/eLife.16620", "url": "https://pubmed.ncbi.nlm.nih.gov/27528194/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27528194", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C60", "CSC1", "CSC2" ] }, { "n": 61, "citation": "Sotillo R, Schvartzman JM, Socci ND et al. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. 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