{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Chromatin Dysregulation as Primary Driver", "entry_form": "phenomenon", "gradeable_restatement": "Chromatin dysregulation can autonomously initiate malignant transformation in mammals and is a primary driver of human cancer rather than a consequence of genetic oncogenic lesions.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Mammalian lineage, baseline genotype, chromatin intervention, induction versus maintenance, exposure and genome-ascertainment horizon fixed before outcomes", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Chromatin Dysregulation as Primary Driver", "central_claim": "Chromatin dysregulation can autonomously initiate malignant transformation in mammals and is a primary driver of human cancer rather than a consequence of genetic oncogenic lesions.", "proposed_mechanism": "Chromatin dysregulation can autonomously initiate malignant transformation in mammals and is a primary driver of human cancer rather than a consequence of genetic oncogenic lesions.", "claimed_scope": "Chromatin dysregulation can autonomously initiate malignant transformation in mammals and is a primary driver of human cancer rather than a consequence of genetic oncogenic lesions.", "claimed_level": [ "initiation", "maintenance", "progression" ], "is_conjunctive": true, "conjunctive_note": "The ranking specifies Cancer Biology; preregister only the cancer arm of the index cancer-and-aging entry. Prior aging reviews remain separate. Epigenetic initiation without a DNA driver is distinct from mutations in chromatin regulators, co-driver activity and therapy-induced plasticity." }, "rubric_routing": { "primary_rubric": "02-cancer-biology.md", "secondary_rubrics": [ "03-epigenetics-gene-regulation.md" ], "index_notes_applied": [ "The ranking specifies Cancer Biology; preregister only the cancer arm of the index cancer-and-aging entry. Prior aging reviews remain separate. Epigenetic initiation without a DNA driver is distinct from mutations in chromatin regulators, co-driver activity and therapy-induced plasticity." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Chromatin abnormalities are pervasive in human tumors.", "subclaim_type": "existence", "scope": "tumor lineage, stage and normal-cell comparator", "claimed_scope": "tumor lineage, stage and normal-cell comparator", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Human epigenomic measurements with composition controls", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Human tumor epigenomic abnormalities are well established observationally; existence does not determine initiating direction, composition or causal primacy." }, { "id": "SC2", "statement": "Transient PRC1 loss creates persistent neoplasia without canonical DNA drivers in Drosophila.", "subclaim_type": "sufficiency", "scope": "fly epithelial genotype and perturbation period", "claimed_scope": "fly epithelial genotype and perturbation period", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Transient endogenous loss, restoration and genomic assessment", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Transient native PH depletion, restoration, persistent neoplasia and serial propagation establish context-bounded fly initiation. Bulk sequencing, repair and karyotype controls narrow detectable shared DNA-driver alternatives without proving absolute absence of every variant or late evolution." }, { "id": "SC3", "statement": "zfh1/JAK-STAT circuitry is necessary for that fly neoplastic state.", "subclaim_type": "necessity", "scope": "defined fly PRC1-loss state", "claimed_scope": "defined fly PRC1-loss state", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Circuit perturbation with tumor-functional rescue", "hsef_level": "Δ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Concomitant zfh1 or Stat co-knockdown significantly reduces growth and partly restores polarity/differentiation; a meaningful causal contribution crosses Δ. Incomplete rescue and intervention during induction do not yet establish complete necessity or isolated late maintenance, so Ε for the exact necessity assertion is not claimed." }, { "id": "SC4", "statement": "Chromatin dysregulation autonomously initiates mammalian cancer and is a primary human-cancer driver.", "subclaim_type": "primacy", "scope": "baseline mammalian lineage, exposure, genotype and ascertainment horizon", "claimed_scope": "baseline mammalian lineage, exposure, genotype and ascertainment horizon", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Transient chromatin-specific induction/restoration with genome-resolved malignant initiation and human equivalents", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Endogenous mouse reprogramming tumors, cis-directed p16 methylation and human MLH1 epimutations are meaningful causal evidence. Genomic engineering, permissive genotype, later genetic hits, transplantation and unresolved driver ascertainment leave the broader autonomy-and-primacy conjunction below Δ." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "The ranking specifies Cancer Biology; preregister only the cancer arm of the index cancer-and-aging entry. Prior aging reviews remain separate. Epigenetic initiation without a DNA driver is distinct from mutations in chromatin regulators, co-driver activity and therapy-induced plasticity.", "primary_subclaim_id": "SC4", "aggregation_derivation": "Scope-matched SC4 yields Γ for the registered mammalian-autonomy and general human-primacy claim. Transient fly initiation is Ε and its circuit perturbations provide Δ causal contribution, while mammalian epimutational and reprogramming causality is retained in defined engineered/predisposition settings. These positive settings do not establish representative autonomous chromatin-first human origin.", "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": "Epigenetic co-driver and maintenance dependency", "core_claim": "Chromatin state and regulators contribute to initiation, persistence and therapy response alongside genotype.", "explains_what_nominal_does_not": "Chromatin state and regulators contribute to initiation, persistence and therapy response alongside genotype.", "strongest_supporting_evidence": [ "Endogenous regulator perturbations, p16 incidence, epimutation predisposition and reversible tumor dependencies converge (25061879,20473912,20951942,27941798,28823558)." ], "strongest_contradictory_evidence": [ "Specific EZH2 suppression fails to halt progression; interactions and lineage boundaries prevent universal necessity (41223330,25625625)." ], "hsef_level_for_this_model": "Ζ", "rationale": "Endogenous regulator perturbations, p16 incidence, epimutation predisposition and reversible tumor dependencies converge (25061879,20473912,20951942,27941798,28823558). Specific EZH2 suppression fails to halt progression; interactions and lineage boundaries prevent universal necessity (41223330,25625625)." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Genetic oncogenesis with epigenetic adaptation", "core_claim": "Genetic lesions can initiate disease and remodel chromatin; adapted states can be causal thereafter.", "explains_what_nominal_does_not": "Genetic lesions can initiate disease and remodel chromatin; adapted states can be causal thereafter.", "strongest_supporting_evidence": [ "KRAS/ARID1A/IDH/H3 models and human second hits demonstrate genotype-first or cooperating routes (35134344,25625625,21130701,20473912)." ], "strongest_contradictory_evidence": [ "Transient fly state and mouse reprogramming/targeted methylation prevent a consequence-only interpretation (38658752,24529372,25061879)." ], "hsef_level_for_this_model": "Ε", "rationale": "KRAS/ARID1A/IDH/H3 models and human second hits demonstrate genotype-first or cooperating routes (35134344,25625625,21130701,20473912). Transient fly state and mouse reprogramming/targeted methylation prevent a consequence-only interpretation (38658752,24529372,25061879)." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Lineage plasticity and reversible state", "core_claim": "Malignant cells can change differentiation and drug tolerance through reversible regulatory programmes.", "explains_what_nominal_does_not": "Malignant cells can change differentiation and drug tolerance through reversible regulatory programmes.", "strongest_supporting_evidence": [ "KDM5A tolerance, RB/p53 prostate lineage and WNT-independent CRC state support functional reversibility (20371346,28059768,28059767,32546576)." ], "strongest_contradictory_evidence": [ "State reversal need not remove DNA lesions or every malignant cell and is not an origin test." ], "hsef_level_for_this_model": "Ε", "rationale": "KDM5A tolerance, RB/p53 prostate lineage and WNT-independent CRC state support functional reversibility (20371346,28059768,28059767,32546576). State reversal need not remove DNA lesions or every malignant cell and is not an origin test." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Chromatin-protein pleiotropy with DNA-damage initiation", "core_claim": "Some chromatin perturbations cause repair failure, insertional events or chromosome changes that cooperate in malignancy.", "explains_what_nominal_does_not": "Some chromatin perturbations cause repair failure, insertional events or chromosome changes that cooperate in malignancy.", "strongest_supporting_evidence": [ "Sustained PH, Dnmt1 and RYBP/TET bodies support genomic alternatives (38888809,12702876,17621273,37272752)." ], "strongest_contradictory_evidence": [ "Transient PH tumors have retained repair and no recurrent detected driver; methylation-specific controls support a direct state effect (38658752,25061879)." ], "hsef_level_for_this_model": "Ε", "rationale": "Sustained PH, Dnmt1 and RYBP/TET bodies support genomic alternatives (38888809,12702876,17621273,37272752). Transient PH tumors have retained repair and no recurrent detected driver; methylation-specific controls support a direct state effect (38658752,25061879)." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Autonomous epigenetic initiation", "core_claim": "Chromatin state alone is the autonomous initiating cause and primary explanation of human cancer.", "explains_what_nominal_does_not": "Chromatin state alone is the autonomous initiating cause and primary explanation of human cancer.", "strongest_supporting_evidence": [ "Fly transient initiation and mammalian reprogramming/methylation are substantial positive cases (38658752,24529372,25061879)." ], "strongest_contradictory_evidence": [ "Engineering, baseline immortalization, later genomic hits, limited ascertainment and nonrepresentative scope block broad primacy (37272752,20473912,32025007)." ], "hsef_level_for_this_model": "Γ", "rationale": "Fly transient initiation and mammalian reprogramming/methylation are substantial positive cases (38658752,24529372,25061879). Engineering, baseline immortalization, later genomic hits, limited ascertainment and nonrepresentative scope block broad primacy (37272752,20473912,32025007)." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Co-driver and genotype-first models overlap, but natural epigenetic first hits and targeted methylation incidence demonstrate that chromatin is not always only a downstream consequence; neither model explains all tumors through one order.", "study_separating_rank1_from_rank2": "Co-driver and genotype-first models overlap, but natural epigenetic first hits and targeted methylation incidence demonstrate that chromatin is not always only a downstream consequence; neither model explains all tumors through one order.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "38658752", "title": "Transient loss of Polycomb components induces an epigenetic cancer fate.", "citation": "Parreno V, Loubiere V, Schuettengruber B et al. Transient loss of Polycomb components induces an epigenetic cancer fate. Nature. 2024.", "doi": "10.1038/s41586-024-07328-w", "pmcid": "PMC11096130", "url": "https://pubmed.ncbi.nlm.nih.gov/38658752/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38658752/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "fly-PRC1-thermosensitive-platform", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Epigenetic perturbations initiate tumours:paragraph0, 1:Epigenetic perturbations initiate tumours:paragraph2, 1:Epigenetic perturbations initiate tumours:paragraph3, 1:Epigenetic perturbations initiate tumours:paragraph4, 1:Epigenetic perturbations initiate tumours:paragraph5, 5:Tumorigenesis requires STAT92E and ZFH1:paragraph0, 5:Tumorigenesis requires STAT92E and ZFH1:paragraph2, 5:Tumorigenesis requires STAT92E and ZFH1:paragraph3, 6:EICs are autonomous immortal tumours:paragraph0, 6:EICs are autonomous immortal tumours:paragraph1, 6:EICs are autonomous immortal tumours:paragraph2. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Transient fly PRC1 loss and restoration", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Transient PRC1 loss followed by PH restoration creates persistent fly neoplasia with serial transplantation and metastasis; bulk genome and repair assays find no recurrent canonical DNA driver.", "what_it_does_not_show": "Four controls and twelve tumors spanning transient/constant depletion constrain detectable shared drivers, not all rare variants; zfh1/Stat concomitant knockdown partially rescues induction and phenotype, not proved complete late-maintenance necessity.", "confounders_present": [ "Four controls and twelve tumors spanning transient/constant depletion constrain detectable shared drivers, not all rare variants; zfh1/Stat concomitant knockdown partially rescues induction and phenotype, not proved complete late-maintenance 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": 2, "pmid": "38888809", "title": "Sustained inactivation of the Polycomb PRC1 complex induces DNA repair defects and genomic instability in epigenetic tumors.", "citation": "Rawal CC, Loubiere V, Butova NL et al. Sustained inactivation of the Polycomb PRC1 complex induces DNA repair defects and genomic instability in epigenetic tumors. Histochemistry and cell biology. 2024.", "doi": "10.1007/s00418-024-02302-z", "pmcid": "PMC11227471", "url": "https://pubmed.ncbi.nlm.nih.gov/38888809/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38888809/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID38746379" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "fly-PRC1-thermosensitive-platform-sustained", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph25, 2:Results:paragraph27, 2:Results:paragraph28, 2:Results:paragraph29. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Sustained fly PH depletion", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Sustained five-day PH depletion causes increased DNA damage, defective break repair and sixfold higher chromosomal rearrangement frequency than controls.", "what_it_does_not_show": "Transient tumor genome stability is cited from Parreno rather than independently replicated here; shared fly platform. Sustained damage does not show all transient epigenetic tumors inevitably acquire drivers.", "confounders_present": [ "Transient tumor genome stability is cited from Parreno rather than independently replicated here; shared fly platform. Sustained damage does not show all transient epigenetic tumors inevitably acquire drivers." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Same thermosensitive PH perturbation system and companion38658752 transient results; sustained-condition genomic damage is new, not a second independent transient initiation replication." ] }, { "n": 3, "pmid": "24529372", "title": "Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation.", "citation": "Ohnishi K, Semi K, Yamamoto T et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell. 2014.", "doi": "10.1016/j.cell.2014.01.005", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24529372/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24529372/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "OSKM-partial-reprogramming-mouse-programme", "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": "Temporally controlled mouse in vivo reprogramming", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Transient reprogramming induces tumors and tumor-derived iPSCs yield nonneoplastic kidney cells.", "what_it_does_not_show": "Engineered expression includes oncogenic/reprogramming factors; normal descendants do not prove no context-dependent sequence changes.", "confounders_present": [ "Engineered expression includes oncogenic/reprogramming factors; normal descendants do not prove no context-dependent sequence 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": 4, "pmid": "34413299", "title": "DMRT1-mediated reprogramming drives development of cancer resembling human germ cell tumors with features of totipotency.", "citation": "Taguchi J, Shibata H, Kabata M et al. DMRT1-mediated reprogramming drives development of cancer resembling human germ cell tumors with features of totipotency. Nature communications. 2021.", "doi": "10.1038/s41467-021-25249-4", "pmcid": "PMC8377058", "url": "https://pubmed.ncbi.nlm.nih.gov/34413299/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34413299/", "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": "OSKM-partial-reprogramming-mouse-programme-germline-followup", "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": "Mouse OSKM and DMRT1 germ-cell-like tumors", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Reprogramming and imprint erasure create tumors with reversible differentiation competence.", "what_it_does_not_show": "Same reprogramming programme; nonphysiological factor induction and lineage scope limit primary human inference.", "confounders_present": [ "Same reprogramming programme; nonphysiological factor induction and lineage scope limit primary human inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Related partial-reprogramming platform to24529372; additional lineage and imprinting assays retain shared intervention failure modes." ] }, { "n": 5, "pmid": "29802314", "title": "In vivo reprogramming drives Kras-induced cancer development.", "citation": "Shibata H, Komura S, Yamada Y et al. In vivo reprogramming drives Kras-induced cancer development. Nature communications. 2018.", "doi": "10.1038/s41467-018-04449-5", "pmcid": "PMC5970190", "url": "https://pubmed.ncbi.nlm.nih.gov/29802314/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29802314/", "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": "PMID29802314", "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": "Kras mutant mouse pancreatic reprogramming/rescue", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Transient dedifferentiation enables mutant-Kras signaling and tumor development; acinar factors inhibit lesions.", "what_it_does_not_show": "Chromatin and genetic lesions cooperate; this supports a causal state contribution rather than autonomous mutation-free initiation.", "confounders_present": [ "Chromatin and genetic lesions cooperate; this supports a causal state contribution rather than autonomous mutation-free 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": 6, "pmid": "37272752", "title": "Deficiency of the Polycomb Protein RYBP and TET Methylcytosine Oxidases Promotes Extensive CpG Island Hypermethylation and Malignant Transformation.", "citation": "Cui W, Huang Z, Jin SG et al. Deficiency of the Polycomb Protein RYBP and TET Methylcytosine Oxidases Promotes Extensive CpG Island Hypermethylation and Malignant Transformation. Cancer research. 2023.", "doi": "10.1158/0008-5472.CAN-23-0269", "pmcid": "PMC10391329", "url": "https://pubmed.ncbi.nlm.nih.gov/37272752/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37272752/", "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": "PMID37272752", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph17, 2:Results:paragraph19, 2:Results:paragraph23. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Genetically disrupted bronchial cells and xenografts", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "RYBP/TET loss induces broad CGI methylation and squamous carcinomas after transplantation.", "what_it_does_not_show": "HBEC3-KT is already telomerase/CDK4-immortalized, four regulator genes are genetically deleted, and QKO cells gain chromosome12p including KRAS; not autonomous non-genetic native initiation.", "confounders_present": [ "HBEC3-KT is already telomerase/CDK4-immortalized, four regulator genes are genetically deleted, and QKO cells gain chromosome12p including KRAS; not autonomous non-genetic native 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": 7, "pmid": "29133799", "title": "Hit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors.", "citation": "Saunderson EA, Stepper P, Gomm JJ et al. Hit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors. Nature communications. 2017.", "doi": "10.1038/s41467-017-01078-2", "pmcid": "PMC5684409", "url": "https://pubmed.ncbi.nlm.nih.gov/29133799/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29133799/", "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": "PMID29133799", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph6, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph13, 1:Results:paragraph14, 1:Results:paragraph17, 1:Results:paragraph24, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Primary healthy-donor breast cells with targeted methylation", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Hit-and-run methylation represses p16 and bypasses senescence.", "what_it_does_not_show": "No anchorage-independent colonies; crisis after60–80days and hTERT only alleviates later arrest. Off-target methylation exists, despite catalytic/dead-editor and different-guide controls.", "confounders_present": [ "No anchorage-independent colonies; crisis after60–80days and hTERT only alleviates later arrest. Off-target methylation exists, despite catalytic/dead-editor and different-guide controls." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "15665276", "title": "Inactivation of imprinted genes induced by cellular stress and tumorigenesis.", "citation": "Pantoja C, de Los Ríos L, Matheu A et al. Inactivation of imprinted genes induced by cellular stress and tumorigenesis. Cancer research. 2005.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15665276/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15665276/", "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": "PMID15665276", "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": "Weak", "system": "Stress-exposed primary mouse fibroblasts and tumors", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Stress triggers imprinted-gene silencing and tumor-associated methylation.", "what_it_does_not_show": "Stress response and tumor signatures do not establish autonomous malignant initiation.", "confounders_present": [ "Stress response and tumor signatures do not establish autonomous malignant 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": 9, "pmid": "20951942", "title": "Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation.", "citation": "Wilson BG, Wang X, Shen X et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer cell. 2010.", "doi": "10.1016/j.ccr.2010.09.006", "pmcid": "PMC2957473", "url": "https://pubmed.ncbi.nlm.nih.gov/20951942/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20951942/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20951942", "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": "Conditional Snf5/Ezh2 mouse models", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Ezh2 loss blocks tumors caused by Snf5 loss.", "what_it_does_not_show": "A genetically initiated chromatin dependency, not non-genetic autonomy; linked erratum PMID absent and correction body unaudited.", "confounders_present": [ "A genetically initiated chromatin dependency, not non-genetic autonomy; linked erratum PMID absent and correction body unaudited." ], "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": "10793065", "title": "Genetic and epigenetic changes in human epithelial cells immortalized by telomerase.", "citation": "Farwell DG, Shera KA, Koop JI et al. Genetic and epigenetic changes in human epithelial cells immortalized by telomerase. The American journal of pathology. 2000.", "doi": "10.1016/S0002-9440(10)65025-0", "pmcid": "PMC1876907", "url": "https://pubmed.ncbi.nlm.nih.gov/10793065/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10793065/", "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": "PMID10793065", "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": "Telomerase-immortalized human epithelial cells", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "p16 methylation or chromosome9p deletion accompanies immortalization and Rb changes.", "what_it_does_not_show": "Clonal chromosomal changes and expression engineering confound purely epigenetic initiation; immortalization is not cancer.", "confounders_present": [ "Clonal chromosomal changes and expression engineering confound purely epigenetic initiation; immortalization is not 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": 11, "pmid": "15488761", "title": "Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis.", "citation": "Chen W, Cooper TK, Zahnow CA et al. Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Cancer cell. 2004.", "doi": "10.1016/j.ccr.2004.08.030", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15488761/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15488761/", "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": "PMID15488761", "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": "Hic1/p53 mouse alleles and human osteosarcoma", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Epigenetic Hic1 loss cooperates with p53 genetic lesions and alters tumor phenotypes.", "what_it_does_not_show": "Predisposed genetic context and cooperating lesions prevent autonomous broad primacy inference.", "confounders_present": [ "Predisposed genetic context and cooperating lesions prevent autonomous broad primacy inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 12, "pmid": "37106015", "title": "The genome-wide mutational consequences of DNA hypomethylation.", "citation": "Besselink N, Keijer J, Vermeulen C et al. The genome-wide mutational consequences of DNA hypomethylation. Scientific reports. 2023.", "doi": "10.1038/s41598-023-33932-3", "pmcid": "PMC10140063", "url": "https://pubmed.ncbi.nlm.nih.gov/37106015/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37106015/", "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": "PMID37106015", "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": "Conditional DNMT1 knockdown and single-cell genome inventories", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Hypomethylation increases chromosomal instability without increased assessed sequence-mutation burden.", "what_it_does_not_show": "Reduced proliferation and culture scope; genomic instability differs from base-mutation burden and malignant transformation was not established.", "confounders_present": [ "Reduced proliferation and culture scope; genomic instability differs from base-mutation burden and malignant transformation was not established." ], "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": "20613874", "title": "Disruption of Dnmt1/PCNA/UHRF1 interactions promotes tumorigenesis from human and mice glial cells.", "citation": "Hervouet E, Lalier L, Debien E et al. Disruption of Dnmt1/PCNA/UHRF1 interactions promotes tumorigenesis from human and mice glial cells. PloS one. 2010.", "doi": "10.1371/journal.pone.0011333", "pmcid": "PMC2894052", "url": "https://pubmed.ncbi.nlm.nih.gov/20613874/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20613874/", "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": "PMID20613874", "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": "Glioma and glial-cell DNMT interaction perturbations", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "DNMT complex disruption links hypomethylation and tumor-like traits to instability.", "what_it_does_not_show": "Genetic and epigenetic alterations jointly occur; phosphorylation perturbs additional functions.", "confounders_present": [ "Genetic and epigenetic alterations jointly occur; phosphorylation perturbs additional functions." ], "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": "16174748", "title": "Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis.", "citation": "Yamada Y, Jackson-Grusby L, Linhart H et al. Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America. 2005.", "doi": "10.1073/pnas.0506612102", "pmcid": "PMC1224663", "url": "https://pubmed.ncbi.nlm.nih.gov/16174748/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16174748/", "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": "PMID16174748", "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": "Apc-Min/Dnmt1 hypomorphic mouse tumors", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Hypomethylation promotes early lesions/liver tumors with Apc LOH but suppresses large intestinal tumors.", "what_it_does_not_show": "Genetic predisposition and stage/lineage-dependent opposing effects defeat universal direction.", "confounders_present": [ "Genetic predisposition and stage/lineage-dependent opposing effects defeat universal 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": "17621273", "title": "Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice.", "citation": "Howard G, Eiges R, Gaudet F et al. Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene. 2008.", "doi": "10.1038/sj.onc.1210631", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17621273/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17621273/", "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": "Dnmt1-hypomorph-mouse-programme-followup", "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": "Dnmt1 hypomorphic mouse lymphomas", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Hypomethylated tumors carry Notch1 retroelement insertion in7of16 plus chromosomal instability.", "what_it_does_not_show": "Shared original Dnmt1 model; followup clarifies genomic contribution rather than independent initial tumor induction.", "confounders_present": [ "Shared original Dnmt1 model; followup clarifies genomic contribution rather than independent initial tumor induction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Related Dnmt1-hypomorphic lymphomas from12702876; insertional drivers add an alternative mechanism, not a separate independent cohort-class proof." ] }, { "n": 16, "pmid": "16204030", "title": "Genetic disruption of cytosine DNA methyltransferase enzymes induces chromosomal instability in human cancer cells.", "citation": "Karpf AR, Matsui S. Genetic disruption of cytosine DNA methyltransferase enzymes induces chromosomal instability in human cancer cells. Cancer research. 2005.", "doi": "10.1158/0008-5472.CAN-05-1961", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16204030/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16204030/", "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": "PMID16204030", "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": "DNMT knockout human HCT116 cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "DNMT deficiency creates spontaneous persistent chromosome translocations and aneuploidy.", "what_it_does_not_show": "Already malignant cell line; genomic consequences support pleiotropic progression, not autonomous native initiation.", "confounders_present": [ "Already malignant cell line; genomic consequences support pleiotropic progression, not autonomous native 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": "23809695", "title": "Specific inhibition of one DNMT1-including complex influences tumor initiation and progression.", "citation": "Cheray M, Pacaud R, Nadaradjane A et al. Specific inhibition of one DNMT1-including complex influences tumor initiation and progression. Clinical epigenetics. 2013.", "doi": "10.1186/1868-7083-5-9", "pmcid": "PMC3727981", "url": "https://pubmed.ncbi.nlm.nih.gov/23809695/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23809695/", "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": "PMID23809695", "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": "DNMT interaction inhibitors and mouse glioma model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Different DNMT interaction disruptions promote tumors or sensitize existing cells to therapy.", "what_it_does_not_show": "Peptide specificity and preexisting tumor context limit autonomy; not all complex disruption has the same direction.", "confounders_present": [ "Peptide specificity and preexisting tumor context limit autonomy; not all complex disruption has the same 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": 18, "pmid": "12702876", "title": "Induction of tumors in mice by genomic hypomethylation.", "citation": "Gaudet F, Hodgson JG, Eden A et al. Induction of tumors in mice by genomic hypomethylation. Science (New York, N.Y.). 2003.", "doi": "10.1126/science.1083558", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12702876/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12702876/", "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": "Dnmt1-hypomorph-mouse-programme", "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": "Dnmt1 hypomorphic autochthonous mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Genome hypomethylation increases aggressive T-cell lymphomas with chromosome15 trisomy.", "what_it_does_not_show": "Genetic Dnmt1 allele and chromosomal instability coexist; does not establish persistent chromatin-only malignant state.", "confounders_present": [ "Genetic Dnmt1 allele and chromosomal instability coexist; does not establish persistent chromatin-only malignant state." ], "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": "22305267", "title": "Bypass of cell cycle arrest induced by transient DNMT1 post-transcriptional silencing triggers aneuploidy in human cells.", "citation": "Barra V, Schillaci T, Lentini L et al. Bypass of cell cycle arrest induced by transient DNMT1 post-transcriptional silencing triggers aneuploidy in human cells. Cell division. 2012.", "doi": "10.1186/1747-1028-7-2", "pmcid": "PMC3292948", "url": "https://pubmed.ncbi.nlm.nih.gov/22305267/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22305267/", "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": "PMID22305267", "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": "DNMT1 depletion in human fibroblasts and HCT116", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Primary cells arrest through p14ARF/p53; checkpoint bypass permits aneuploidy.", "what_it_does_not_show": "Additional suppressor depletion is required for bypass and malignant initiation is not demonstrated.", "confounders_present": [ "Additional suppressor depletion is required for bypass and malignant initiation is not demonstrated." ], "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": "21130701", "title": "Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation.", "citation": "Figueroa ME, Abdel-Wahab O, Lu C et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer cell. 2010.", "doi": "10.1016/j.ccr.2010.11.015", "pmcid": "PMC4105845", "url": "https://pubmed.ncbi.nlm.nih.gov/21130701/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21130701/", "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": "PMID21130701", "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 AML profiling and IDH/TET cellular tests", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Mutant IDH produces2HG, inhibits TET and causes methylation/differentiation defects.", "what_it_does_not_show": "Genetic enzyme alteration precedes chromatin changes; marker/differentiation changes are not sole malignant initiation evidence.", "confounders_present": [ "Genetic enzyme alteration precedes chromatin changes; marker/differentiation changes are not sole malignant initiation evidence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "25398940", "title": "IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition.", "citation": "Kernytsky A, Wang F, Hansen E et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood. 2015.", "doi": "10.1182/blood-2013-10-533604", "pmcid": "PMC4295919", "url": "https://pubmed.ncbi.nlm.nih.gov/25398940/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25398940/", "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": "PMID25398940", "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": "IDH2-mutant leukemia cells and inhibitor reversal", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "IDH inhibition reverses histone changes rapidly and DNA changes more slowly.", "what_it_does_not_show": "Engineered preexisting leukemia background and upstream genetic driver; methylation reversal is not proof of epigenetic origin.", "confounders_present": [ "Engineered preexisting leukemia background and upstream genetic driver; methylation reversal is not proof of epigenetic origin." ], "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": "24065766", "title": "Induction of sarcomas by mutant IDH2.", "citation": "Lu C, Venneti S, Akalin A et al. Induction of sarcomas by mutant IDH2. Genes & development. 2013.", "doi": "10.1101/gad.226753.113", "pmcid": "PMC3792475", "url": "https://pubmed.ncbi.nlm.nih.gov/24065766/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24065766/", "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": "PMID24065766", "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": "Mutant-IDH mesenchymal cells and implanted sarcomas", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Mutant IDH drives methylation, differentiation block and implanted sarcomas.", "what_it_does_not_show": "Neomorphic genetic lesion is the initiating intervention; transplantation scope and pleiotropic metabolism remain.", "confounders_present": [ "Neomorphic genetic lesion is the initiating intervention; transplantation scope and pleiotropic metabolism remain." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 23, "pmid": "22797305", "title": "A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers.", "citation": "Lee RS, Stewart C, Carter SL et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. The Journal of clinical investigation. 2012.", "doi": "10.1172/JCI64400", "pmcid": "PMC3408754", "url": "https://pubmed.ncbi.nlm.nih.gov/22797305/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22797305/", "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": "PMID22797305", "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": "Weak", "system": "Thirty-five human rhabdoid tumor exomes", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Rhabdoid cancers can have very few coding mutations with recurrent biallelic SMARCB1 loss.", "what_it_does_not_show": "Low mutation burden is not mutation-free; exomes do not assess all structural/noncoding events.", "confounders_present": [ "Low mutation burden is not mutation-free; exomes do not assess all structural/noncoding events." ], "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": "27941797", "title": "SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation.", "citation": "Wang X, Lee RS, Alver BH et al. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nature genetics. 2017.", "doi": "10.1038/ng.3746", "pmcid": "PMC5285474", "url": "https://pubmed.ncbi.nlm.nih.gov/27941797/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27941797/", "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": "PMID27941797", "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 rhabdoid cells and enhancer perturbations", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "SMARCB1 loss remodels enhancer targeting and creates lineage-specific survival dependencies.", "what_it_does_not_show": "Genetic loss underlies epigenetic effects and survival is distinct from autonomous initiation.", "confounders_present": [ "Genetic loss underlies epigenetic effects and survival is distinct from autonomous 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": 25, "pmid": "31015438", "title": "BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors.", "citation": "Wang X, Wang S, Troisi EC et al. BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors. Nature communications. 2019.", "doi": "10.1038/s41467-019-09891-7", "pmcid": "PMC6479050", "url": "https://pubmed.ncbi.nlm.nih.gov/31015438/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31015438/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID31558726" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31015438", "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": "Rhabdoid CRISPR dependency screens", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "BRD9 complex integrity rather than its bromodomain mediates a selective tumor survival dependency.", "what_it_does_not_show": "Genetic SMARCB1 context and protein scaffolding; linked author-correction body unaudited.", "confounders_present": [ "Genetic SMARCB1 context and protein scaffolding; linked author-correction body unaudited." ], "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": "26569409", "title": "Hepatocyte-Specific Arid1a Deficiency Initiates Mouse Steatohepatitis and Hepatocellular Carcinoma.", "citation": "Fang JZ, Li C, Liu XY et al. Hepatocyte-Specific Arid1a Deficiency Initiates Mouse Steatohepatitis and Hepatocellular Carcinoma. PloS one. 2015.", "doi": "10.1371/journal.pone.0143042", "pmcid": "PMC4646347", "url": "https://pubmed.ncbi.nlm.nih.gov/26569409/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26569409/", "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": "PMID26569409", "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": "Hepatocyte Arid1a knockout mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Arid1a loss produces inflammation, steatohepatitis and HCC.", "what_it_does_not_show": "A genetic chromatin-regulator deletion with inflammatory intermediates, not isolated non-genetic autonomous initiation.", "confounders_present": [ "A genetic chromatin-regulator deletion with inflammatory intermediates, not isolated non-genetic autonomous 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": 27, "pmid": "26069190", "title": "ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors.", "citation": "Shen J, Peng Y, Wei L et al. ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors. Cancer discovery. 2015.", "doi": "10.1158/2159-8290.CD-14-0849", "pmcid": "PMC4497871", "url": "https://pubmed.ncbi.nlm.nih.gov/26069190/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26069190/", "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": "PMID26069190", "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": "ARID1A DNA repair and PARP response models", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "ARID1A regulates ATR-associated repair and checkpoint function and creates PARP sensitivity.", "what_it_does_not_show": "Chromatin proteins also govern genome integrity; tumor response is not initiation attribution.", "confounders_present": [ "Chromatin proteins also govern genome integrity; tumor response is not initiation attribution." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 28, "pmid": "27941798", "title": "ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice.", "citation": "Mathur R, Alver BH, San Roman AK et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nature genetics. 2017.", "doi": "10.1038/ng.3744", "pmcid": "PMC5285448", "url": "https://pubmed.ncbi.nlm.nih.gov/27941798/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27941798/", "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": "PMID27941798", "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": "Endogenous Arid1a mouse colon deletion", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Loss causes invasive colon tumors without canonical APC pathway deregulation and alters enhancers.", "what_it_does_not_show": "Arid1a deletion is itself genetic; colon/small-intestine difference limits broad tissue primacy.", "confounders_present": [ "Arid1a deletion is itself genetic; colon/small-intestine difference limits broad tissue 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": 29, "pmid": "25625625", "title": "Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling.", "citation": "Chandler RL, Damrauer JS, Raab JR et al. Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling. Nature communications. 2015.", "doi": "10.1038/ncomms7118", "pmcid": "PMC4308813", "url": "https://pubmed.ncbi.nlm.nih.gov/25625625/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25625625/", "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": "PMID25625625", "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": "Arid1a/Pik3ca ovarian mouse genotypes", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Arid1a alone fails tumor induction; concurrent Pik3ca activation enables rapid OCCC.", "what_it_does_not_show": "Context-specific epistasis and inflammation undermine a universal autonomous chromatin-only account.", "confounders_present": [ "Context-specific epistasis and inflammation undermine a universal autonomous chromatin-only account." ], "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": "26552009", "title": "SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2.", "citation": "Kim KH, Kim W, Howard TP et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nature medicine. 2015.", "doi": "10.1038/nm.3968", "pmcid": "PMC4886303", "url": "https://pubmed.ncbi.nlm.nih.gov/26552009/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26552009/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ExpressionOfConcernIn: PMID42760338" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26552009", "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": "Weak", "system": "SWI/SNF-mutant lines and xenografts", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "The original report proposed catalytic and noncatalytic EZH2 dependencies.", "what_it_does_not_show": "Editorial Expression of Concern42760338; excluded from threshold-crossing evidence pending notice investigation, although the original abstract/status record was examined.", "confounders_present": [ "Editorial Expression of Concern42760338; excluded from threshold-crossing evidence pending notice investigation, although the original abstract/status record was examined." ], "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": [ "Editorial Expression of Concern42760338; excluded from qualifying evidence." ] }, { "n": 31, "pmid": "33545065", "title": "H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.", "citation": "Haag D, Mack N, Benites Goncalves da Silva P et al. H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model. Cancer cell. 2021.", "doi": "10.1016/j.ccell.2021.01.005", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33545065/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33545065/", "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": "PMID33545065", "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": "Endogenous H3K27M human iPSC models and orthotopic xenografts", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "H3K27M effects depend on cell type and tumors require NSC context with TP53 loss.", "what_it_does_not_show": "Genetic histone and TP53 lesions; engineered transplantation does not establish native epigenetic-only initiation.", "confounders_present": [ "Genetic histone and TP53 lesions; engineered transplantation does not establish native epigenetic-only 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": 32, "pmid": "35524725", "title": "A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M.", "citation": "Tomita Y, Shimazu Y, Somasundaram A et al. A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M. Glia. 2022.", "doi": "10.1002/glia.24189", "pmcid": "PMC9546478", "url": "https://pubmed.ncbi.nlm.nih.gov/35524725/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35524725/", "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": "PMID35524725", "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": "Neonatal brainstem mouse glioma models", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "H3K27M changes latency in Nestin progenitors but has reduced effects in Olig2 progenitors.", "what_it_does_not_show": "Growth-factor induction and p53 deletion cooperate; cell-of-origin specificity defeats uniform primacy.", "confounders_present": [ "Growth-factor induction and p53 deletion cooperate; cell-of-origin specificity defeats uniform 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": 33, "pmid": "34294917", "title": "Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells.", "citation": "Brien GL, Bressan RB, Monger C et al. Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells. Nature genetics. 2021.", "doi": "10.1038/s41588-021-00897-w", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34294917/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34294917/", "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": "PMID34294917", "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 hindbrain stem cells with H3K27M", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Histone mutation locks immature lineage through enhancer and PRC2 disruption.", "what_it_does_not_show": "Mutation-induced chromatin response; state maintenance and mechanistic culture assays do not establish mutation-free native initiation.", "confounders_present": [ "Mutation-induced chromatin response; state maintenance and mechanistic culture assays do not establish mutation-free native 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": 34, "pmid": "32546576", "title": "Lineage Reversion Drives WNT Independence in Intestinal Cancer.", "citation": "Han T, Goswami S, Hu Y et al. Lineage Reversion Drives WNT Independence in Intestinal Cancer. Cancer discovery. 2020.", "doi": "10.1158/2159-8290.CD-19-1536", "pmcid": "PMC7541594", "url": "https://pubmed.ncbi.nlm.nih.gov/32546576/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32546576/", "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": "PMID32546576", "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": "Mutant intestinal organoids and in vivo tumors", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Genetic lesions plus transient TGF-beta create persistent YAP/TAZ lineage reversion and WNT-independent resistance.", "what_it_does_not_show": "A state transition in genetically altered tumors, not primary non-genetic initiation.", "confounders_present": [ "A state transition in genetically altered tumors, not primary non-genetic 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": 35, "pmid": "28059768", "title": "SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer.", "citation": "Mu P, Zhang Z, Benelli M et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science (New York, N.Y.). 2017.", "doi": "10.1126/science.aah4307", "pmcid": "PMC5247742", "url": "https://pubmed.ncbi.nlm.nih.gov/28059768/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28059768/", "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": "PMID28059768", "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": "TP53/RB1 deficient prostate models and rescue", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "SOX2-dependent lineage switching creates antiandrogen resistance and genetic/SOX2 restoration reverses it.", "what_it_does_not_show": "Maintenance and therapy resistance in genetically altered models; not cancer origin.", "confounders_present": [ "Maintenance and therapy resistance in genetically altered models; not cancer origin." ], "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": "28059767", "title": "Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance.", "citation": "Ku SY, Rosario S, Wang Y et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science (New York, N.Y.). 2017.", "doi": "10.1126/science.aah4199", "pmcid": "PMC5367887", "url": "https://pubmed.ncbi.nlm.nih.gov/28059767/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28059767/", "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": "PMID28059767", "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": "mouse endogenous", "decisive_perturbation": true, "endogenous": true, "direction": "supporting", "what_it_shows": "Rb1/Trp53 loss in Pten-initiated prostate tumors promotes lineage plasticity/metastasis and resistance; EZH2 inhibition restores AR and antiandrogen sensitivity.", "what_it_does_not_show": "Genetic lesions initiate the model; regulatory restoration affects progression/resistance, not autonomous epigenetic origin. Related28059768 programme and author summary28401192 are not independent replications.", "confounders_present": [ "Genetic lesions initiate the model; regulatory restoration affects progression/resistance, not autonomous epigenetic origin. Related28059768 programme and author summary28401192 are not independent replications." ], "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": "28823558", "title": "Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression.", "citation": "Cimmino L, Dolgalev I, Wang Y et al. Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell. 2017.", "doi": "10.1016/j.cell.2017.07.032", "pmcid": "PMC5755977", "url": "https://pubmed.ncbi.nlm.nih.gov/28823558/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28823558/", "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": "PMID28823558", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia. Communications biology. 2020.", "doi": "10.1038/s42003-020-01220-9", "pmcid": "PMC7477582", "url": "https://pubmed.ncbi.nlm.nih.gov/32895473/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32895473/", "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": "PMID32895473", "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": "TET2-mutant myeloid models", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Ascorbate effects vary with mutation and acetylation state.", "what_it_does_not_show": "Biochemical context limits general treatment or causal restoration claims; no primary human cancer origin demonstrated.", "confounders_present": [ "Biochemical context limits general treatment or causal restoration claims; no primary human cancer origin demonstrated." ], "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": "41223330", "title": "EZH2 Suppression Diversifies Prostate Cancer Lineage Variant Evolution and Lacks Efficacy in Inhibiting Disease Progression.", "citation": "Jacobi JJ, Wadosky KM, Jaiswal N et al. EZH2 Suppression Diversifies Prostate Cancer Lineage Variant Evolution and Lacks Efficacy in Inhibiting Disease Progression. Cancer research. 2026.", "doi": "10.1158/0008-5472.CAN-25-2747", "pmcid": "PMC12940094", "url": "https://pubmed.ncbi.nlm.nih.gov/41223330/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41223330/", "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": "PMID41223330", "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": "Genetically engineered prostate mice and clinical samples", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "EZH2 suppression expands lineage diversity without suppressing progression/resistance.", "what_it_does_not_show": "Selected advanced disease context; null efficacy is not absence of all EZH2 functions.", "confounders_present": [ "Selected advanced disease context; null efficacy is not absence of all EZH2 functions." ], "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": "41379538", "title": "The Histone Methyltransferase KMT2D Is a Critical Mediator of Lineage Plasticity and Therapeutic Response in Castration-Resistant Prostate Cancer.", "citation": "Kittane S, Ladewig E, Li T et al. The Histone Methyltransferase KMT2D Is a Critical Mediator of Lineage Plasticity and Therapeutic Response in Castration-Resistant Prostate Cancer. Cancer research. 2026.", "doi": "10.1158/0008-5472.CAN-25-2053", "pmcid": "PMC12900249", "url": "https://pubmed.ncbi.nlm.nih.gov/41379538/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41379538/", "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": "PMID41379538", "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": "CRPC lines, patient organoids and samples", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "KMT2D sustains both AR-dependent and stem-like chromatin states and therapeutic response.", "what_it_does_not_show": "Protein loss and cofactor recruitment pleiotropy; advanced-state maintenance, not initial origin.", "confounders_present": [ "Protein loss and cofactor recruitment pleiotropy; advanced-state maintenance, not initial origin." ], "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": "41507359", "title": "KMT2D loss drives adeno-to-squamous transition and sensitizes TKI-resistant lung cancer to AURKA inhibition.", "citation": "Chen N, Fang M, Zhong L et al. KMT2D loss drives adeno-to-squamous transition and sensitizes TKI-resistant lung cancer to AURKA inhibition. Cell death and differentiation. 2026.", "doi": "10.1038/s41418-025-01657-7", "pmcid": "PMC13342116", "url": "https://pubmed.ncbi.nlm.nih.gov/41507359/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41507359/", "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": "PMID41507359", "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": "TKI-resistant lung organoids, xenografts and orthotopic tumors", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "KMT2D loss promotes squamous switching and an AURKA dependency.", "what_it_does_not_show": "Genetic/state cooperation and therapy-selected lineage transition; also changes kinase stability apart from histone chemistry.", "confounders_present": [ "Genetic/state cooperation and therapy-selected lineage transition; also changes kinase stability apart from histone chemistry." ], "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": "24371281", "title": "Immortality, but not oncogenic transformation, of primary human cells leads to epigenetic reprogramming of DNA methylation and gene expression.", "citation": "Gordon K, Clouaire T, Bao XX et al. Immortality, but not oncogenic transformation, of primary human cells leads to epigenetic reprogramming of DNA methylation and gene expression. Nucleic acids research. 2014.", "doi": "10.1093/nar/gkt1351", "pmcid": "PMC3973294", "url": "https://pubmed.ncbi.nlm.nih.gov/24371281/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24371281/", "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": "PMID24371281", "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": "Primary human immortalization and oncogene comparisons", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Extended lifespan induces methylation changes while oncogenes confer malignancy traits.", "what_it_does_not_show": "Culture-adaptation model; epigenetic changes can reflect proliferation history rather than primary malignant origin.", "confounders_present": [ "Culture-adaptation model; epigenetic changes can reflect proliferation history rather than primary malignant origin." ], "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": "34649604", "title": "KrasG12D induces changes in chromatin territories that differentially impact early nuclear reprogramming in pancreatic cells.", "citation": "Mathison AJ, Kerketta R, de Assuncao TM et al. KrasG12D induces changes in chromatin territories that differentially impact early nuclear reprogramming in pancreatic cells. Genome biology. 2021.", "doi": "10.1186/s13059-021-02498-6", "pmcid": "PMC8518179", "url": "https://pubmed.ncbi.nlm.nih.gov/34649604/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34649604/", "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": "PMID34649604", "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": "Inducible Kras pancreatic cell models", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Oncogenic Kras precedes a coordinated time-dependent chromatin response.", "what_it_does_not_show": "Enhancer-mark modeling and cell systems do not isolate primary chromatin initiation.", "confounders_present": [ "Enhancer-mark modeling and cell systems do not isolate primary chromatin 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": 44, "pmid": "35134344", "title": "Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity.", "citation": "Kadur Lakshminarasimha Murthy P, Xi R, Arguijo D et al. Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity. Developmental cell. 2022.", "doi": "10.1016/j.devcel.2022.01.006", "pmcid": "PMC8938988", "url": "https://pubmed.ncbi.nlm.nih.gov/35134344/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35134344/", "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": "PMID35134344", "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": "Kras mouse models, human tissues and cells", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "AP1/SWI-SNF remodeling drives lineage-specific transformation downstream of Kras.", "what_it_does_not_show": "A real chromatin co-driver within an upstream genetic programme, not mutually exclusive genetic-versus-epigenetic origin.", "confounders_present": [ "A real chromatin co-driver within an upstream genetic programme, not mutually exclusive genetic-versus-epigenetic origin." ], "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": "31285370", "title": "BAP1 Loss Is Associated with DNA Methylomic Repatterning in Highly Aggressive Class 2 Uveal Melanomas.", "citation": "Field MG, Kuznetsov JN, Bussies PL et al. BAP1 Loss Is Associated with DNA Methylomic Repatterning in Highly Aggressive Class 2 Uveal Melanomas. Clinical cancer research : an official journal of the American Association for Cancer Research. 2019.", "doi": "10.1158/1078-0432.CCR-19-0366", "pmcid": "PMC6744995", "url": "https://pubmed.ncbi.nlm.nih.gov/31285370/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31285370/", "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": "PMID31285370", "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 uveal tumors and inducible BAP1 depletion", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "BAP1 loss reproduces tumor methylomic repatterning.", "what_it_does_not_show": "Chromosome3 loss and BAP1 mutation precede the inferred epigenomic transition; depletion does not reconstruct full initiation.", "confounders_present": [ "Chromosome3 loss and BAP1 mutation precede the inferred epigenomic transition; depletion does not reconstruct full 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": 46, "pmid": "31371502", "title": "Paradoxical association of TET loss of function with genome-wide DNA hypomethylation.", "citation": "López-Moyado IF, Tsagaratou A, Yuita H et al. Paradoxical association of TET loss of function with genome-wide DNA hypomethylation. Proceedings of the National Academy of Sciences of the United States of America. 2019.", "doi": "10.1073/pnas.1903059116", "pmcid": "PMC6708373", "url": "https://pubmed.ncbi.nlm.nih.gov/31371502/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31371502/", "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": "PMID31371502", "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": "Tet2/3-deficient mouse lymphoma genomic analysis", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "TET loss creates compartment-specific hyper/hypomethylation, repeat activation and genomic alterations.", "what_it_does_not_show": "Genetic deficiency and acquired alterations coexist; undermines a generic no-DNA-change assumption.", "confounders_present": [ "Genetic deficiency and acquired alterations coexist; undermines a generic no-DNA-change assumption." ], "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": "31164355", "title": "A Model System for Studying the DNMT3A Hotspot Mutation (DNMT3AR882) Demonstrates a Causal Relationship between Its Dominant-Negative Effect and Leukemogenesis.", "citation": "Lu R, Wang J, Ren Z et al. A Model System for Studying the DNMT3A Hotspot Mutation (DNMT3AR882) Demonstrates a Causal Relationship between Its Dominant-Negative Effect and Leukemogenesis. Cancer research. 2019.", "doi": "10.1158/0008-5472.CAN-18-3275", "pmcid": "PMC6897384", "url": "https://pubmed.ncbi.nlm.nih.gov/31164355/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31164355/", "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": "PMID31164355", "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": "DNMT3A mutant leukemia cells and mouse assays", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "DNMT3A dominant-negative activity and enhancer hypomethylation support leukemogenic function.", "what_it_does_not_show": "Genetic mutation and preexisting leukemia-cell background; synergy with IDH mutation constrains autonomy.", "confounders_present": [ "Genetic mutation and preexisting leukemia-cell background; synergy with IDH mutation constrains autonomy." ], "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": "30361341", "title": "The chromatin accessibility landscape of primary human cancers.", "citation": "Corces MR, Granja JM, Shams S et al. The chromatin accessibility landscape of primary human cancers. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aav1898", "pmcid": "PMC6408149", "url": "https://pubmed.ncbi.nlm.nih.gov/30361341/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30361341/", "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": "TCGA-accessible-chromatin-cohort", "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": "Weak", "system": "Four-hundred-ten primary human tumor accessibility maps", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Tumors show lineage-specific accessibility and candidate regulatory differences.", "what_it_does_not_show": "Cross-sectional TCGA data and bulk composition do not determine initiation order or chromatin-only primacy.", "confounders_present": [ "Cross-sectional TCGA data and bulk composition do not determine initiation order or chromatin-only 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": 49, "pmid": "39661721", "title": "Control of Cellular Differentiation Trajectories for Cancer Reversion.", "citation": "Gong JR, Lee CK, Kim HM et al. Control of Cellular Differentiation Trajectories for Cancer Reversion. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2025.", "doi": "10.1002/advs.202402132", "pmcid": "PMC11744559", "url": "https://pubmed.ncbi.nlm.nih.gov/39661721/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39661721/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID42138980" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39661721", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Result:paragraph64, 1:Result:paragraph65, 1:Result:paragraph66, 1:Result:paragraph68, 1:Result:paragraph70, 1:Result:paragraph72. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "CRC regulator knockdown and tumor-cell xenografts", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Combined regulator inhibition induces enterocyte-like differentiation and reduces malignancy.", "what_it_does_not_show": "Three established cancer cell lines and short xenograft growth tests show normal-like differentiation/reduced proliferation, not origin, eradication or normal genome restoration; correction42138980 body unaudited.", "confounders_present": [ "Three established cancer cell lines and short xenograft growth tests show normal-like differentiation/reduced proliferation, not origin, eradication or normal genome restoration; correction42138980 body unaudited." ], "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": [ "Final publication replaces earlier manuscript; correction42138980 metadata-only." ] }, { "n": 50, "pmid": "39478232", "title": "Progressive plasticity during colorectal cancer metastasis.", "citation": "Moorman A, Benitez EK, Cambuli F et al. Progressive plasticity during colorectal cancer metastasis. Nature. 2025.", "doi": "10.1038/s41586-024-08150-0", "pmcid": "PMC11754107", "url": "https://pubmed.ncbi.nlm.nih.gov/39478232/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39478232/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37662289", "ErratumIn: PMID39789339", "ErratumIn: PMID42557335" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39478232", "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": "Matched normal/primary/metastatic CRC and organoids", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Conserved mutations coexist with increasing fetal-like and noncanonical cell-state plasticity.", "what_it_does_not_show": "Metastatic progression is distinct from primary initiation; two author corrections and preprint replacement logged.", "confounders_present": [ "Metastatic progression is distinct from primary initiation; two author corrections and preprint replacement logged." ], "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": [ "Final replaces37662289 preprint; corrections39789339/42557335 metadata-only." ] }, { "n": 51, "pmid": "6185846", "title": "Hypomethylation distinguishes genes of some human cancers from their normal counterparts.", "citation": "Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983.", "doi": "10.1038/301089a0", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/6185846/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/6185846/", "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": "PMID6185846", "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": "Weak", "system": "Untreated human cancers with adjacent normal tissues", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Specific-gene hypomethylation is observed in four of five cases.", "what_it_does_not_show": "Small observational series, tissue composition and temporal direction unresolved.", "confounders_present": [ "Small observational series, tissue composition and temporal direction unresolved." ], "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": "20473912", "title": "De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one.", "citation": "Goel A, Nguyen TP, Leung HC et al. De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one. International journal of cancer. 2011.", "doi": "10.1002/ijc.25422", "pmcid": "PMC3794437", "url": "https://pubmed.ncbi.nlm.nih.gov/20473912/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20473912/", "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": "constitutional-MLH1-carrier-programme", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Human constitutional MLH1 epimutation natural experiments", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Systemic allelic methylation predisposes to very early cancers, usually with a genetic second hit.", "what_it_does_not_show": "Two new early-onset constitutional epimutation cases have somatic loss of the opposite active allele; earlier tumors include predicted deleterious MLH1 missense changes. Epigenetic first-hit predisposition is real, while later genetic hits and unknown trans cues remain.", "confounders_present": [ "Two new early-onset constitutional epimutation cases have somatic loss of the opposite active allele; earlier tumors include predicted deleterious MLH1 missense changes. Epigenetic first-hit predisposition is real, while later genetic hits and unknown trans cues remain." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "30283143", "title": "Primary constitutional MLH1 epimutations: a focal epigenetic event.", "citation": "Dámaso E, Castillejo A, Arias MDM et al. Primary constitutional MLH1 epimutations: a focal epigenetic event. British journal of cancer. 2018.", "doi": "10.1038/s41416-018-0019-8", "pmcid": "PMC6203851", "url": "https://pubmed.ncbi.nlm.nih.gov/30283143/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30283143/", "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": "constitutional-MLH1-carrier-mechanistic-followup", "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": "MLH1 epimutation carriers and locus characterization", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Most analyzed carriers lack cis nucleotide/structural variants; methylation can erase between generations.", "what_it_does_not_show": "Restricted locus ascertainment and rare predisposition, not general human-cancer primacy or absence of tumor second hits.", "confounders_present": [ "Restricted locus ascertainment and rare predisposition, not general human-cancer primacy or absence of tumor second hits." ], "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": [ "Constitutional carrier follow-up; overlapping carrier literature is not independent population-level risk quantification." ] }, { "n": 54, "pmid": "25191524", "title": "Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors.", "citation": "Timp W, Bravo HC, McDonald OG et al. Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors. Genome medicine. 2014.", "doi": "10.1186/s13073-014-0061-y", "pmcid": "PMC4154522", "url": "https://pubmed.ncbi.nlm.nih.gov/25191524/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25191524/", "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": "PMID25191524", "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": "Weak", "system": "Multicancer methylation and premalignant comparisons", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Large hypomethylated blocks occur early across sampled common solid tumors.", "what_it_does_not_show": "Early association does not establish causal dominance; array coverage and normal-cell composition limit inference.", "confounders_present": [ "Early association does not establish causal dominance; array coverage and normal-cell composition limit inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 55, "pmid": "32024998", "title": "Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.", "citation": "Rodriguez-Martin B, Alvarez EG, Baez-Ortega A et al. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nature genetics. 2020.", "doi": "10.1038/s41588-019-0562-0", "pmcid": "PMC7058536", "url": "https://pubmed.ncbi.nlm.nih.gov/32024998/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32024998/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID36944736" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PCAWG-2658-cohort", "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": "Weak", "system": "PCAWG whole genomes and retrotransposition analyses", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Retroelement events can generate oncogenic deletions, translocations and amplifications.", "what_it_does_not_show": "Shared consortium cohort and genomic reconstruction; cannot prove every tumor requires these events and correction body is unaudited.", "confounders_present": [ "Shared consortium cohort and genomic reconstruction; cannot prove every tumor requires these events and correction body is unaudited." ], "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": [ "PCAWG cohort overlaps32025007/32025013; one shared pan-cancer cohort, not three independent patient series." ] }, { "n": 56, "pmid": "32025013", "title": "The evolutionary history of 2,658 cancers.", "citation": "Gerstung M, Jolly C, Leshchiner I et al. The evolutionary history of 2,658 cancers. Nature. 2020.", "doi": "10.1038/s41586-019-1907-7", "pmcid": "PMC7054212", "url": "https://pubmed.ncbi.nlm.nih.gov/32025013/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32025013/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID36697833" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PCAWG-2658-cohort", "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": "Weak", "system": "PCAWG evolutionary reconstruction", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Driver sequences often precede diagnosis and later evolution gains instability.", "what_it_does_not_show": "Model-based timing and shared cohort; cannot exclude earlier unobserved epigenetic predisposition and correction body unaudited.", "confounders_present": [ "Model-based timing and shared cohort; cannot exclude earlier unobserved epigenetic predisposition and correction body unaudited." ], "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": [ "Shared PCAWG cohort and genome calls." ] }, { "n": 57, "pmid": "20371346", "title": "A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.", "citation": "Sharma SV, Lee DY, Li B et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010.", "doi": "10.1016/j.cell.2010.02.027", "pmcid": "PMC2851638", "url": "https://pubmed.ncbi.nlm.nih.gov/20371346/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20371346/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20371346", "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 cancer-cell drug-tolerance perturbations", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Reversible chromatin states mediate drug tolerance in a small cancer-cell fraction.", "what_it_does_not_show": "Preexisting malignancy and treatment challenge; cell-state reversibility does not show a non-genetic initial cause.", "confounders_present": [ "Preexisting malignancy and treatment challenge; cell-state reversibility does not show a non-genetic initial cause." ], "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": "32025007", "title": "Pan-cancer analysis of whole genomes.", "citation": "ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature. 2020.", "doi": "10.1038/s41586-020-1969-6", "pmcid": "PMC7025898", "url": "https://pubmed.ncbi.nlm.nih.gov/32025007/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32025007/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID36697834" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PCAWG-2658-cohort", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 6:PCAWG tumours with no apparent drivers. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "PCAWG tumor-normal whole genome resource", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Most cancers have identified drivers, but around5percent have none recognized.", "what_it_does_not_show": "Five-point-three percent remain without identified drivers after technical corrections; TERT coverage, normal-panel filtering and aneuploidy expose limits. No identified driver is not proof of no genomic contribution. Shared PCAWG cohort.", "confounders_present": [ "Five-point-three percent remain without identified drivers after technical corrections; TERT coverage, normal-panel filtering and aneuploidy expose limits. No identified driver is not proof of no genomic contribution. Shared PCAWG cohort." ], "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": [ "Shared PCAWG cohort; residual unidentified-driver cases are not proof of genetic absence." ] }, { "n": 59, "pmid": "39196936", "title": "Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch.", "citation": "Gretarsson KH, Abini-Agbomson S, Gloor SL et al. Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch. Science advances. 2024.", "doi": "10.1126/sciadv.adp0975", "pmcid": "PMC11352909", "url": "https://pubmed.ncbi.nlm.nih.gov/39196936/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39196936/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID38562823" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39196936", "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": "DNMT3A-nucleosome structure and cellular rescue", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Dual histone-ubiquitin/acidic-patch recognition recruits DNMT3A and creates promoter methylation.", "what_it_does_not_show": "Mechanistic methylation and differentiation blockade, not autochthonous malignant initiation; final replaces preprint.", "confounders_present": [ "Mechanistic methylation and differentiation blockade, not autochthonous malignant initiation; final replaces preprint." ], "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": [ "Final replaces38562823 preprint." ] }, { "n": 60, "pmid": "25061879", "title": "Targeted p16(Ink4a) epimutation causes tumorigenesis and reduces survival in mice.", "citation": "Yu DH, Waterland RA, Zhang P et al. Targeted p16(Ink4a) epimutation causes tumorigenesis and reduces survival in mice. The Journal of clinical investigation. 2014.", "doi": "10.1172/JCI76507", "pmcid": "PMC4151219", "url": "https://pubmed.ncbi.nlm.nih.gov/25061879/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25061879/", "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": "PMID25061879", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph38, 0:Publisher HTML paragraphs:paragraph39, 0:Publisher HTML paragraphs:paragraph40, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph46. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Targeted p16 methylation in mice", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Targeted p16 methylation and silencing increase spontaneous tumor incidence and shorten survival in mice; homozygous engineered allele yields6/22 tumors versus0/18 wild-type.", "what_it_does_not_show": "An inserted cis DNA element recruits methylation; small mixed-background cohorts and combined knockout experiments do not establish mutation-free spontaneous human cancer primacy. Methylation reversal rescues expression in cells, not demonstrated tumor reversal in vivo.", "confounders_present": [ "An inserted cis DNA element recruits methylation; small mixed-background cohorts and combined knockout experiments do not establish mutation-free spontaneous human cancer primacy. Methylation reversal rescues expression in cells, not demonstrated tumor reversal in vivo." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 65, "verified": 65, "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": "Human tumor epigenomic abnormalities are well established observationally; existence does not determine initiating direction, composition or causal primacy.", "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": "Endogenous mouse reprogramming tumors, cis-directed p16 methylation and human MLH1 epimutations are meaningful causal evidence. Genomic engineering, permissive genotype, later genetic hits, transplantation and unresolved driver ascertainment leave the broader autonomy-and-primacy conjunction below Δ.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Chromatin dysregulation can autonomously initiate malignant transformation in mammals and is a primary driver of human cancer rather than a consequence of genetic oncogenic lesions.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Association cap Β governs SC1 direction-neutral tumor signatures. Fly transient restoration crosses endogenous Δ/Ε in its own scope; partial circuit rescue crosses Δ contribution but not full necessity. Genetically engineered regulator dependencies, human predisposition and targeted p16 methylation collectively support stronger co-driver causality. Their success is not capped simply because one source is a transplant; the broad SC4 claim remains Γ because the combined evidence still lacks representative autonomous human initiation.", "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": [ "Cross-sectional abnormalities and composition effects do not establish origin." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Human tumor epigenomic abnormalities are well established observationally; existence does not determine initiating direction, composition or causal primacy.", "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": "PMID38658752", "gamma_hard_rules_triggered": [], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Transient native PH depletion, restoration, persistent neoplasia and serial propagation establish context-bounded fly initiation. Bulk sequencing, repair and karyotype controls narrow detectable shared DNA-driver alternatives without proving absolute absence of every variant or late evolution.", "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": "PMID38658752", "gamma_hard_rules_triggered": [ "Partial concomitant rescue does not identify isolated late-maintenance necessity." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Concomitant zfh1 or Stat co-knockdown significantly reduces growth and partly restores polarity/differentiation; a meaningful causal contribution crosses Δ. Incomplete rescue and intervention during induction do not yet establish complete necessity or isolated late maintenance, so Ε for the exact necessity assertion is not claimed.", "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": [ "Broad primacy is not established by defined mouse epimutation/predisposition settings, genetic regulator deletion or transplantation." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Endogenous mouse reprogramming tumors, cis-directed p16 methylation and human MLH1 epimutations are meaningful causal evidence. Genomic engineering, permissive genotype, later genetic hits, transplantation and unresolved driver ascertainment leave the broader autonomy-and-primacy conjunction below Δ.", "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": "Human longitudinal lineage-resolved epigenomic evidence distinguishing state, composition and initiating direction." }, { "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": [ "[1] Transient PRC1 loss followed by PH restoration creates persistent fly neoplasia with serial transplantation and metastasis; bulk genome and repair assays find no recurrent canonical DNA driver." ], "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": [ "[1] Transient PRC1 loss followed by PH restoration creates persistent fly neoplasia with serial transplantation and metastasis; bulk genome and repair assays find no recurrent canonical DNA driver." ], "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": "no", "supporting_evidence": [ "[1] Transient PRC1 loss followed by PH restoration creates persistent fly neoplasia with serial transplantation and metastasis; bulk genome and repair assays find no recurrent canonical DNA driver." ], "what_would_cross_it": "Independent transient perturbation/restoration in another fly lineage, serial genomic lineage tracking and orthogonal local chromatin rescue." }, { "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] Transient PRC1 loss followed by PH restoration creates persistent fly neoplasia with serial transplantation and metastasis; bulk genome and repair assays find no recurrent canonical DNA driver." ], "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": "no", "supporting_evidence": [ "[1] Transient PRC1 loss followed by PH restoration creates persistent fly neoplasia with serial transplantation and metastasis; bulk genome and repair assays find no recurrent canonical DNA driver." ], "what_would_cross_it": "Separate late circuit interruption after PH restoration, matched controls and circuit-specific rescue that abolish and restore the defined malignant phenotype rather than only reduce induction." }, { "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": "Independent endogenous mammalian transient state-specific initiation/restoration with clone-resolved genomic ascertainment, malignant lineage tracking and representative human natural equivalents that distinguish epigenetic first hit from genetic cooperation." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "PH restoration and restrictive-temperature graft hosts prevent continued initiator depletion; multiple backgrounds and another PRC1 component narrow construct-specific errors (38658752).", "Stat/zfh1 knockdown alone has no obvious eye phenotype; combined perturbation partly rescues PH phenotype, not complete abolition (38658752).", "p16 control insert and cellular demethylation restore methylation-specific interpretation; mixed backgrounds and small tumor cohorts remain limits (25061879).", "Dead-editor, no-guide, dCas9-only and different-guide breast controls support targeted methylation contribution; no anchorage growth is a meaningful negative (29133799).", "Bronchial parental cells fail to form tumors; QKO transformation remains in CDK4/telomerase cells and carries12p gain (37272752).", "ARID1A deletion alone fails to initiate the specified ovarian disease without PIK3CA cooperation (25625625).", "Expression-of-Concern source is not used to cross a threshold (26552009)." ], "note": "Cancer arm only; no aging conclusion. Define species, tissue, genotype, endogenous/transplantation setting, induction/restoration stage and genome detection before outcomes. Fly autonomous persistence, engineered mouse incidence, human epigenetic predisposition and existing-tumor plasticity retain separate scopes. No requirement that all human cancers contain an identified mutation, and no inference that unassigned drivers prove mutation-free origin." }, "falsification_patterns_met": [ { "pattern": "Senescence escape without malignant transformation", "evidence": "Primary healthy breast methylation targeting produces proliferation but no anchorage-independent growth and later crisis (29133799).", "downgrade_applied": false }, { "pattern": "Transformation requires genetic cooperation or genomic changes", "evidence": "Immortalized bronchial QKO cells gain12p; ARID1A ovary needs PIK3CA; H3K27M models require origin/genotype cooperation (37272752,25625625,33545065,35524725).", "downgrade_applied": false }, { "pattern": "Sustained chromatin perturbation creates genetic instability", "evidence": "Constant PH depletion disrupts break repair and karyotype, unlike transient companion assays; Dnmt1 lymphomas acquire trisomy/insertional events (38888809,12702876,17621273).", "downgrade_applied": false }, { "pattern": "Chromatin intervention does not generally improve therapy response", "evidence": "EZH2 suppression expands prostate lineages without blocking progression or antiandrogen resistance in defined models (41223330).", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Mutation of chromatin regulators relabeled as mutation-free initiation", "where": "ARID1A, SMARCB1, H3K27M, IDH and TET/DNMT genetic models." }, { "pitfall": "Absence of identified drivers treated as absence of all genomic contribution", "where": "Bulk fly assays and residual PCAWG cases; coverage/purity and unknown biology remain." }, { "pitfall": "Existing-tumor reversion treated as origin or cure", "where": "Drug-tolerant states, lineage plasticity and three-cell-line normal-like CRC reversion." }, { "pitfall": "Co-knockdown during induction treated as late-maintenance necessity", "where": "Parreno zfh1/Stat partial-rescue assays." }, { "pitfall": "Editorial warning ignored", "where": "26552009 has Expression of Concern42760338; not a threshold-crossing source." } ], "causal_tally_audit": { "tally_claimed_by_document": 38, "tally_after_audit": 38, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Fly companion results share a platform; OSKM follow-ups share induction; PCAWG papers share genomes; report count is not independent causal replication.", "The EZH2 Expression-of-Concern paper is explicitly excluded from discriminating threshold crossings." ] }, "steelman": { "case_one_rung_higher": "A Δ steelman cites native mouse partial reprogramming tumors, p16 methylation-linked incidence and human MLH1 predisposition, plus the fly restoration experiment. These justify causal credit for narrower epigenetic initiation/predisposition and defeat a consequence-only dismissal.", "case_one_rung_lower": "A Β steelman treats human chromatin signatures as correlations and genetic regulator models as ordinary mutation-driven disease. It misses intervention-linked mouse incidence, reversibility, human epigenetic first hits and causal native state dependencies.", "which_rejected": "Γ is retained for SC4 rather than erasing mammalian causality or upgrading general primacy. Δ is not crossed for the exact autonomy-and-primary-human-driver conjunction; Β is too low for the mechanistic and intervention base.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Independent native mammalian transient chromatin-state induction and restoration with longitudinal malignant lineage and genome ascertainment" }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Evidence density and reproducibility set the band, not correctness and not reviewer access depth: human tumour epigenome mapping and the genetic chromatin-regulator literature are large and well replicated, but the evidence bearing on the registered autonomy claim is thin and hard to reproduce - one fly programme, one engineered p16-methylation cohort of 6/22 versus 0/18 on a small mixed background, reprogramming tumours sharing one OSKM programme, an already-immortalised bronchial line, bulk-assay detection bounds standing in for absence of driver variants, and one source under an Editorial Expression of Concern.", "rests_on_non_peer_reviewed_work": false, "rationale": "Scope-matched SC4 yields Γ for the registered mammalian-autonomy and general human-primacy claim. Transient fly initiation is Ε and its circuit perturbations provide Δ causal contribution, while mammalian epimutational and reprogramming causality is retained in defined engineered/predisposition settings. These positive settings do not establish representative autonomous chromatin-first human origin." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Step1 consequence-only fails because defined state interventions and epimutations can precede and alter malignancy. Step2 mere association is exceeded. Step3 general primary/rate-limiting status is not established; step4 uniform permissive necessity is not established. Step5 captures context-dependent co-driver and maintenance/plasticity roles before the tournament. Defined fly initiation and p16/MLH1 first-hit settings can have earlier causal roles without assigning them to all human cancers.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The named artifacts are completed primary perturbation studies (the 2024 transient-PRC1 fly experiment and its companion sustained-depletion report, the 2026 prostate EZH2 study) that refine mechanistic and functional boundaries; no work is named that is presently being run and could cross the next threshold for the registered mammalian-autonomy claim.", "justification": "The named artifacts are completed primary perturbation studies (the 2024 transient-PRC1 fly experiment and its companion sustained-depletion report, the 2026 prostate EZH2 study) that refine mechanistic and functional boundaries; no work is named that is presently being run and could cross the next threshold for the registered mammalian-autonomy claim." }, "stability": { "value": "Stable", "trigger": "No named pending result is asserted to be likely to move the registered score imminently.", "justification": "No named pending result is asserted to be likely to move the registered score imminently." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Independent native mammalian transient chromatin-state induction and restoration with longitudinal malignant lineage and genome ascertainment", "readout": "Persistent endogenous malignant behavior after state-initiator restoration, clone-linked genome/epigenome trajectories and context-matched normal controls.", "critical_control": "Match genotype, baseline lineage, regulator abundance and nonchromatin functions; use orthogonal local-state rescue and genomic-driver positive/negative controls.", "supporting_result": "Multiple independent native lineages acquire persistent malignancy after a reversible state-only initiating change, with convergent controls excluding measured genetic and pleiotropic alternatives; human natural equivalents show the same order.", "falsifying_result": "Malignancy requires permissive genomic lesions, fails after state restoration, tracks acquired genetic events or shows only reversible proliferation/differentiation without malignant behavior." } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Independent mammalian transient chromatin-state initiation/restoration beyond one reprogramming or inserted-sequence platform.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Clone-linked genome ascertainment for rare subclones, structural/noncoding events and post-initiation evolution rather than absolute mutation absence assertions.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Human constitutional epimutation incidence, penetrance and pre-tumor trajectories with identified versus unknown cis/trans causes separated.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Late interruption and matched rescue of fly zfh1/JAK-STAT after PH restoration, distinct from co-knockdown during induction.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Local methylation/histone interventions preserving regulator abundance and repair/nonchromatin functions.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Malignant-function tests distinguished from senescence bypass, anchorage growth, short xenograft growth and normal-like markers.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Prespecified tissue/genotype boundaries for chromatin regulator single-hit versus genetic-cooperation models.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Durability, residual malignant cells and genome state after regulatory reversion or therapy-associated lineage switching.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 9", "statement": "Independent cohort/platform replication with explicit shared TCGA/PCAWG/OSKM/fly components.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 10", "statement": "Full original supplements, unresolved correction bodies and the EZH2 editorial Expression-of-Concern investigation before publication-grade reliance.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-08", "reviewer": "Codex", "evidence_base_note": "60 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; primary leads were resolved to canonical originals before counting. See scispace-discovery.json.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "The index 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": "Human constitutional MLH1 epimutations and endogenous mammalian partial reprogramming/engineered methylation are live causal equivalents, not dismissed for lack of a clinical RCT. Multiple genotypes and orthogonal mouse perturbations establish epigenetic contribution. They do not resolve mutation-free autonomy or the representative primacy of chromatin-first human initiation." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Human constitutional MLH1 epimutations and endogenous mammalian partial reprogramming/engineered methylation are live causal equivalents, not dismissed for lack of a clinical RCT. Multiple genotypes and orthogonal mouse perturbations establish epigenetic contribution. They do not resolve mutation-free autonomy or the representative primacy of chromatin-first human initiation." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Human constitutional MLH1 epimutations and endogenous mammalian partial reprogramming/engineered methylation are live causal equivalents, not dismissed for lack of a clinical RCT. Multiple genotypes and orthogonal mouse perturbations establish epigenetic contribution. They do not resolve mutation-free autonomy or the representative primacy of chromatin-first human initiation." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Human constitutional MLH1 epimutations and endogenous mammalian partial reprogramming/engineered methylation are live causal equivalents, not dismissed for lack of a clinical RCT. Multiple genotypes and orthogonal mouse perturbations establish epigenetic contribution. They do not resolve mutation-free autonomy or the representative primacy of chromatin-first human initiation." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Human constitutional MLH1 epimutations and endogenous mammalian partial reprogramming/engineered methylation are live causal equivalents, not dismissed for lack of a clinical RCT. Multiple genotypes and orthogonal mouse perturbations establish epigenetic contribution. They do not resolve mutation-free autonomy or the representative primacy of chromatin-first human initiation." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 60, "claims_total": 65, "claims_verified": 65, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 60, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Transient PRC1 loss followed by PH restoration creates persistent fly neoplasia with serial transplantation and metastasis; bulk genome and repair assays find no recurrent canonical DNA driver. Four controls and twelve tumors spanning transient/constant depletion constrain detectable shared drivers, not all rare variants; zfh1/Stat concomitant knockdown partially rescues induction and phenotype, not proved complete late-maintenance necessity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Epigenetic perturbations initiate tumours:paragraph0, 1:Epigenetic perturbations initiate tumours:paragraph2, 1:Epigenetic perturbations initiate tumours:paragraph3, 1:Epigenetic perturbations initiate tumours:paragraph4, 1:Epigenetic perturbations initiate tumours:paragraph5, 5:Tumorigenesis requires STAT92E and ZFH1:paragraph0, 5:Tumorigenesis requires STAT92E and ZFH1:paragraph2, 5:Tumorigenesis requires STAT92E and ZFH1:paragraph3, 6:EICs are autonomous immortal tumours:paragraph0, 6:EICs are autonomous immortal tumours:paragraph1, 6:EICs are autonomous immortal tumours:paragraph2. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C2", "text": "Sustained five-day PH depletion causes increased DNA damage, defective break repair and sixfold higher chromosomal rearrangement frequency than controls. Transient tumor genome stability is cited from Parreno rather than independently replicated here; shared fly platform. Sustained damage does not show all transient epigenetic tumors inevitably acquire drivers.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph25, 2:Results:paragraph27, 2:Results:paragraph28, 2:Results:paragraph29. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C3", "text": "Transient reprogramming induces tumors and tumor-derived iPSCs yield nonneoplastic kidney cells. Engineered expression includes oncogenic/reprogramming factors; normal descendants do not prove no context-dependent sequence changes.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "Reprogramming and imprint erasure create tumors with reversible differentiation competence. Same reprogramming programme; nonphysiological factor induction and lineage scope limit primary human inference.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "Transient dedifferentiation enables mutant-Kras signaling and tumor development; acinar factors inhibit lesions. Chromatin and genetic lesions cooperate; this supports a causal state contribution rather than autonomous mutation-free initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "RYBP/TET loss induces broad CGI methylation and squamous carcinomas after transplantation. HBEC3-KT is already telomerase/CDK4-immortalized, four regulator genes are genetically deleted, and QKO cells gain chromosome12p including KRAS; not autonomous non-genetic native initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph17, 2:Results:paragraph19, 2:Results:paragraph23. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C7", "text": "Hit-and-run methylation represses p16 and bypasses senescence. No anchorage-independent colonies; crisis after60–80days and hTERT only alleviates later arrest. Off-target methylation exists, despite catalytic/dead-editor and different-guide controls.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph6, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph13, 1:Results:paragraph14, 1:Results:paragraph17, 1:Results:paragraph24, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C8", "text": "Stress triggers imprinted-gene silencing and tumor-associated methylation. Stress response and tumor signatures do not establish autonomous malignant initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "Ezh2 loss blocks tumors caused by Snf5 loss. A genetically initiated chromatin dependency, not non-genetic autonomy; linked erratum PMID absent and correction body unaudited.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "p16 methylation or chromosome9p deletion accompanies immortalization and Rb changes. Clonal chromosomal changes and expression engineering confound purely epigenetic initiation; immortalization is not cancer.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "Epigenetic Hic1 loss cooperates with p53 genetic lesions and alters tumor phenotypes. Predisposed genetic context and cooperating lesions prevent autonomous broad primacy inference.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "Hypomethylation increases chromosomal instability without increased assessed sequence-mutation burden. Reduced proliferation and culture scope; genomic instability differs from base-mutation burden and malignant transformation was not established.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "DNMT complex disruption links hypomethylation and tumor-like traits to instability. Genetic and epigenetic alterations jointly occur; phosphorylation perturbs additional functions.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "Hypomethylation promotes early lesions/liver tumors with Apc LOH but suppresses large intestinal tumors. Genetic predisposition and stage/lineage-dependent opposing effects defeat universal direction.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "Hypomethylated tumors carry Notch1 retroelement insertion in7of16 plus chromosomal instability. Shared original Dnmt1 model; followup clarifies genomic contribution rather than independent initial tumor induction.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "DNMT deficiency creates spontaneous persistent chromosome translocations and aneuploidy. Already malignant cell line; genomic consequences support pleiotropic progression, not autonomous native initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "Different DNMT interaction disruptions promote tumors or sensitize existing cells to therapy. Peptide specificity and preexisting tumor context limit autonomy; not all complex disruption has the same direction.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "Genome hypomethylation increases aggressive T-cell lymphomas with chromosome15 trisomy. Genetic Dnmt1 allele and chromosomal instability coexist; does not establish persistent chromatin-only malignant state.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "Primary cells arrest through p14ARF/p53; checkpoint bypass permits aneuploidy. Additional suppressor depletion is required for bypass and malignant initiation is not demonstrated.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "Mutant IDH produces2HG, inhibits TET and causes methylation/differentiation defects. Genetic enzyme alteration precedes chromatin changes; marker/differentiation changes are not sole malignant initiation evidence.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "IDH inhibition reverses histone changes rapidly and DNA changes more slowly. Engineered preexisting leukemia background and upstream genetic driver; methylation reversal is not proof of epigenetic origin.", "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": "Mutant IDH drives methylation, differentiation block and implanted sarcomas. Neomorphic genetic lesion is the initiating intervention; transplantation scope and pleiotropic metabolism remain.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C23", "text": "Rhabdoid cancers can have very few coding mutations with recurrent biallelic SMARCB1 loss. Low mutation burden is not mutation-free; exomes do not assess all structural/noncoding events.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "SMARCB1 loss remodels enhancer targeting and creates lineage-specific survival dependencies. Genetic loss underlies epigenetic effects and survival is distinct from autonomous initiation.", "carries_number": true, "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": "BRD9 complex integrity rather than its bromodomain mediates a selective tumor survival dependency. Genetic SMARCB1 context and protein scaffolding; linked author-correction body unaudited.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "Arid1a loss produces inflammation, steatohepatitis and HCC. A genetic chromatin-regulator deletion with inflammatory intermediates, not isolated non-genetic autonomous initiation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C27", "text": "ARID1A regulates ATR-associated repair and checkpoint function and creates PARP sensitivity. Chromatin proteins also govern genome integrity; tumor response is not initiation attribution.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "Loss causes invasive colon tumors without canonical APC pathway deregulation and alters enhancers. Arid1a deletion is itself genetic; colon/small-intestine difference limits broad tissue primacy.", "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": "Arid1a alone fails tumor induction; concurrent Pik3ca activation enables rapid OCCC. Context-specific epistasis and inflammation undermine a universal autonomous chromatin-only account.", "carries_number": true, "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": "The original report proposed catalytic and noncatalytic EZH2 dependencies. Editorial Expression of Concern42760338; excluded from threshold-crossing evidence pending notice investigation, although the original abstract/status record was examined.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "H3K27M effects depend on cell type and tumors require NSC context with TP53 loss. Genetic histone and TP53 lesions; engineered transplantation does not establish native epigenetic-only initiation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C32", "text": "H3K27M changes latency in Nestin progenitors but has reduced effects in Olig2 progenitors. Growth-factor induction and p53 deletion cooperate; cell-of-origin specificity defeats uniform primacy.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "Histone mutation locks immature lineage through enhancer and PRC2 disruption. Mutation-induced chromatin response; state maintenance and mechanistic culture assays do not establish mutation-free native initiation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C34", "text": "Genetic lesions plus transient TGF-beta create persistent YAP/TAZ lineage reversion and WNT-independent resistance. A state transition in genetically altered tumors, not primary non-genetic initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C35", "text": "SOX2-dependent lineage switching creates antiandrogen resistance and genetic/SOX2 restoration reverses it. Maintenance and therapy resistance in genetically altered models; not cancer origin.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "Rb1/Trp53 loss in Pten-initiated prostate tumors promotes lineage plasticity/metastasis and resistance; EZH2 inhibition restores AR and antiandrogen sensitivity. Genetic lesions initiate the model; regulatory restoration affects progression/resistance, not autonomous epigenetic origin. Related28059768 programme and author summary28401192 are not independent replications.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C37", "text": "Endogenous Tet2 restoration reverses aberrant self-renewal and suppresses leukemia progression. Predisposed/genetically altered disease and vitamin-C pleiotropy; maintenance response does not identify original initiator.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C38", "text": "Ascorbate effects vary with mutation and acetylation state. Biochemical context limits general treatment or causal restoration claims; no primary human cancer origin demonstrated.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C39", "text": "EZH2 suppression expands lineage diversity without suppressing progression/resistance. Selected advanced disease context; null efficacy is not absence of all EZH2 functions.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C40", "text": "KMT2D sustains both AR-dependent and stem-like chromatin states and therapeutic response. Protein loss and cofactor recruitment pleiotropy; advanced-state maintenance, not initial origin.", "carries_number": true, "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": "KMT2D loss promotes squamous switching and an AURKA dependency. Genetic/state cooperation and therapy-selected lineage transition; also changes kinase stability apart from histone chemistry.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C42", "text": "Extended lifespan induces methylation changes while oncogenes confer malignancy traits. Culture-adaptation model; epigenetic changes can reflect proliferation history rather than primary malignant origin.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C43", "text": "Oncogenic Kras precedes a coordinated time-dependent chromatin response. Enhancer-mark modeling and cell systems do not isolate primary chromatin initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "AP1/SWI-SNF remodeling drives lineage-specific transformation downstream of Kras. A real chromatin co-driver within an upstream genetic programme, not mutually exclusive genetic-versus-epigenetic origin.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "BAP1 loss reproduces tumor methylomic repatterning. Chromosome3 loss and BAP1 mutation precede the inferred epigenomic transition; depletion does not reconstruct full initiation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "TET loss creates compartment-specific hyper/hypomethylation, repeat activation and genomic alterations. Genetic deficiency and acquired alterations coexist; undermines a generic no-DNA-change assumption.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "DNMT3A dominant-negative activity and enhancer hypomethylation support leukemogenic function. Genetic mutation and preexisting leukemia-cell background; synergy with IDH mutation constrains autonomy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "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": "Tumors show lineage-specific accessibility and candidate regulatory differences. Cross-sectional TCGA data and bulk composition do not determine initiation order or chromatin-only primacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "Combined regulator inhibition induces enterocyte-like differentiation and reduces malignancy. Three established cancer cell lines and short xenograft growth tests show normal-like differentiation/reduced proliferation, not origin, eradication or normal genome restoration; correction42138980 body unaudited.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Result:paragraph64, 1:Result:paragraph65, 1:Result:paragraph66, 1:Result:paragraph68, 1:Result:paragraph70, 1:Result:paragraph72. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C50", "text": "Conserved mutations coexist with increasing fetal-like and noncanonical cell-state plasticity. Metastatic progression is distinct from primary initiation; two author corrections and preprint replacement logged.", "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": "Specific-gene hypomethylation is observed in four of five cases. Small observational series, tissue composition and temporal direction unresolved.", "carries_number": false, "load_bearing_for": [ "SC1" ], "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": "Systemic allelic methylation predisposes to very early cancers, usually with a genetic second hit. Two new early-onset constitutional epimutation cases have somatic loss of the opposite active allele; earlier tumors include predicted deleterious MLH1 missense changes. Epigenetic first-hit predisposition is real, while later genetic hits and unknown trans cues remain.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C53", "text": "Most analyzed carriers lack cis nucleotide/structural variants; methylation can erase between generations. Restricted locus ascertainment and rare predisposition, not general human-cancer primacy or absence of tumor second hits.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "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": "Large hypomethylated blocks occur early across sampled common solid tumors. Early association does not establish causal dominance; array coverage and normal-cell composition limit inference.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C55", "text": "Retroelement events can generate oncogenic deletions, translocations and amplifications. Shared consortium cohort and genomic reconstruction; cannot prove every tumor requires these events and correction body is unaudited.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C56", "text": "Driver sequences often precede diagnosis and later evolution gains instability. Model-based timing and shared cohort; cannot exclude earlier unobserved epigenetic predisposition and correction body unaudited.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C57", "text": "Reversible chromatin states mediate drug tolerance in a small cancer-cell fraction. Preexisting malignancy and treatment challenge; cell-state reversibility does not show a non-genetic initial cause.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C58", "text": "Most cancers have identified drivers, but around5percent have none recognized. Five-point-three percent remain without identified drivers after technical corrections; TERT coverage, normal-panel filtering and aneuploidy expose limits. No identified driver is not proof of no genomic contribution. Shared PCAWG cohort.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 6:PCAWG tumours with no apparent drivers. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C59", "text": "Dual histone-ubiquitin/acidic-patch recognition recruits DNMT3A and creates promoter methylation. Mechanistic methylation and differentiation blockade, not autochthonous malignant initiation; final replaces preprint.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "Targeted p16 methylation and silencing increase spontaneous tumor incidence and shorten survival in mice; homozygous engineered allele yields6/22 tumors versus0/18 wild-type. An inserted cis DNA element recruits methylation; small mixed-background cohorts and combined knockout experiments do not establish mutation-free spontaneous human cancer primacy. Methylation reversal rescues expression in cells, not demonstrated tumor reversal in vivo.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph38, 0:Publisher HTML paragraphs:paragraph39, 0:Publisher HTML paragraphs:paragraph40, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph46. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC1", "text": "Human tumor epigenomic abnormalities are well established observationally; existence does not determine initiating direction, composition or causal primacy.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC2", "text": "Transient native PH depletion, restoration, persistent neoplasia and serial propagation establish context-bounded fly initiation. Bulk sequencing, repair and karyotype controls narrow detectable shared DNA-driver alternatives without proving absolute absence of every variant or late evolution.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC3", "text": "Concomitant zfh1 or Stat co-knockdown significantly reduces growth and partly restores polarity/differentiation; a meaningful causal contribution crosses Δ. Incomplete rescue and intervention during induction do not yet establish complete necessity or isolated late maintenance, so Ε for the exact necessity assertion is not claimed.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC4", "text": "Endogenous mouse reprogramming tumors, cis-directed p16 methylation and human MLH1 epimutations are meaningful causal evidence. Genomic engineering, permissive genotype, later genetic hits, transplantation and unresolved driver ascertainment leave the broader autonomy-and-primacy conjunction below Δ.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 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": "CH", "text": "Epigenetic changes can cause cancer predisposition and sustain malignant states; autonomous chromatin-first initiation as the primary explanation of human cancer remains unestablished.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 3, 60, 52, 6, 58 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-09", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Parreno V, Loubiere V, Schuettengruber B et al. Transient loss of Polycomb components induces an epigenetic cancer fate. Nature. 2024.", "tier": "A", "kind": "primary", "pmid": "38658752", "doi": "10.1038/s41586-024-07328-w", "url": "https://pubmed.ncbi.nlm.nih.gov/38658752/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "fly-PRC1-thermosensitive-platform", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Epigenetic perturbations initiate tumours:paragraph0, 1:Epigenetic perturbations initiate tumours:paragraph2, 1:Epigenetic perturbations initiate tumours:paragraph3, 1:Epigenetic perturbations initiate tumours:paragraph4, 1:Epigenetic perturbations initiate tumours:paragraph5, 5:Tumorigenesis requires STAT92E and ZFH1:paragraph0, 5:Tumorigenesis requires STAT92E and ZFH1:paragraph2, 5:Tumorigenesis requires STAT92E and ZFH1:paragraph3, 6:EICs are autonomous immortal tumours:paragraph0, 6:EICs are autonomous immortal tumours:paragraph1, 6:EICs are autonomous immortal tumours:paragraph2. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC2", "CSC3", "CSC4", "CH" ] }, { "n": 2, "citation": "Rawal CC, Loubiere V, Butova NL et al. Sustained inactivation of the Polycomb PRC1 complex induces DNA repair defects and genomic instability in epigenetic tumors. Histochemistry and cell biology. 2024.", "tier": "A", "kind": "primary", "pmid": "38888809", "doi": "10.1007/s00418-024-02302-z", "url": "https://pubmed.ncbi.nlm.nih.gov/38888809/", "status_flags": [ "UpdateOf: PMID38746379" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "fly-PRC1-thermosensitive-platform-sustained", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph25, 2:Results:paragraph27, 2:Results:paragraph28, 2:Results:paragraph29. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC2", "CSC3", "CSC4" ] }, { "n": 3, "citation": "Ohnishi K, Semi K, Yamamoto T et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell. 2014.", "tier": "A", "kind": "primary", "pmid": "24529372", "doi": "10.1016/j.cell.2014.01.005", "url": "https://pubmed.ncbi.nlm.nih.gov/24529372/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "OSKM-partial-reprogramming-mouse-programme", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC4", "CH" ] }, { "n": 4, "citation": "Taguchi J, Shibata H, Kabata M et al. DMRT1-mediated reprogramming drives development of cancer resembling human germ cell tumors with features of totipotency. Nature communications. 2021.", "tier": "A", "kind": "primary", "pmid": "34413299", "doi": "10.1038/s41467-021-25249-4", "url": "https://pubmed.ncbi.nlm.nih.gov/34413299/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "OSKM-partial-reprogramming-mouse-programme-germline-followup", "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", "CSC4" ] }, { "n": 5, "citation": "Shibata H, Komura S, Yamada Y et al. In vivo reprogramming drives Kras-induced cancer development. Nature communications. 2018.", "tier": "A", "kind": "primary", "pmid": "29802314", "doi": "10.1038/s41467-018-04449-5", "url": "https://pubmed.ncbi.nlm.nih.gov/29802314/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29802314", "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", "CSC4" ] }, { "n": 6, "citation": "Cui W, Huang Z, Jin SG et al. Deficiency of the Polycomb Protein RYBP and TET Methylcytosine Oxidases Promotes Extensive CpG Island Hypermethylation and Malignant Transformation. 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