{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Epigenetic Field Cancerization", "entry_form": "phenomenon", "gradeable_restatement": "Spontaneous promoter hypermethylation in morphologically normal epithelium independently initiates and sustains pre-neoplastic clonal field expansion and subsequent carcinogenesis.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Organ, exposure history, acquired versus constitutional epimutation, engineered genotype and incident versus metachronous endpoint", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Epigenetic Field Cancerization", "central_claim": "Spontaneous promoter hypermethylation in morphologically normal epithelium independently initiates and sustains pre-neoplastic clonal field expansion and subsequent carcinogenesis.", "proposed_mechanism": "Spontaneous promoter hypermethylation in morphologically normal epithelium independently initiates and sustains pre-neoplastic clonal field expansion and subsequent carcinogenesis.", "claimed_scope": "Acquired promoter hypermethylation in morphologically normal epithelium; organ, prior inflammatory exposure, genotype and prospective endpoint specified before outcomes.", "claimed_level": [ "initiation", "progression" ], "is_conjunctive": true, "conjunctive_note": "Register all five index subclaims. SC5 gates spontaneous mutation-independent epithelial initiation; engineered single-locus methylation, inflammatory induction, prediction and abnormal methylation presence are distinct. Age/exposure/genotype controls are antecedent, not responder-defined." }, "rubric_routing": { "primary_rubric": "02-cancer-biology.md", "secondary_rubrics": [ "03-epigenetics-gene-regulation.md" ], "index_notes_applied": [ "Register all five index subclaims. SC5 gates spontaneous mutation-independent epithelial initiation; engineered single-locus methylation, inflammatory induction, prediction and abnormal methylation presence are distinct. Age/exposure/genotype controls are antecedent, not responder-defined." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Aberrant DNA methylation is present in morphologically normal epithelium at elevated tumor risk.", "subclaim_type": "existence", "scope": "organ, age, exposure and normal histology", "claimed_scope": "organ, age, exposure and normal histology", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Age-matched epithelial methylomes", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Normal epithelial methylation fields are reproducible, spatially measurable and often associated with neoplasia. This is robust existence/association evidence, with locus and organ-specific nulls; the Β cancer-association cap does not deny their existence." }, { "id": "SC2", "statement": "Targeted tumor-suppressor promoter hypermethylation raises spontaneous tumor incidence in vivo.", "subclaim_type": "sufficiency", "scope": "methylated locus, mammalian lineage and genotype", "claimed_scope": "methylated locus, mammalian lineage and genotype", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Locus-targeted methylation and tumor incidence", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Endogenous-locus engineered p16 methylation raises spontaneous tumor incidence without a required engineered oncogene. Inserted-sequence controls and reactivation distinguish silencing from simple insertion effects. Small mixed-background cohorts and lack of adult native field demethylation/incidence rescue keep this at context-specific Ε." }, { "id": "SC3", "statement": "Chronic inflammation causally induces durable epithelial DNA methylation.", "subclaim_type": "mechanism", "scope": "inflammation/exposure and tissue defined before outcome", "claimed_scope": "inflammation/exposure and tissue defined before outcome", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Induction/withdrawal with epithelial lineage measurement", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Inflammation suppression despite retained colonization, exposure-duration contrasts, withdrawal and human longitudinal biopsies establish defined inflammatory routes to methylation. Persistence is partly marker-specific; broad immunosuppression, repair changes and limited original-body access prevent a universally resolved induction mechanism." }, { "id": "SC4", "statement": "Methylation in normal mucosa predicts metachronous cancer.", "subclaim_type": "existence", "scope": "baseline cancer/exposure, organ and follow-up horizon", "claimed_scope": "baseline cancer/exposure, organ and follow-up horizon", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Prospective normal mucosa measurements", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Several prospective cohorts demonstrate later cancer or neoplasia associations, including independent primary-incidence and metachronous cohorts. The Β association cap applies to causal interpretation, not to the validated predictive signal. Marker alteration has not itself been selectively shown to change human incidence." }, { "id": "SC5", "statement": "Spontaneous endogenous epimutations independently initiate and sustain clonal field expansion.", "subclaim_type": "primacy", "scope": "morphologically normal epithelial clones with baseline genome ascertainment", "claimed_scope": "morphologically normal epithelial clones with baseline genome ascertainment", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Lineage-resolved genome/epigenome and epimutation-specific functional rescue", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Organoid aging-like methylation provides a plausible functional precursor and rare constitutional epimutations establish epigenetic predisposition. No examined positive native epithelial lineage study isolates spontaneously arising methylation as independently initiating and sustaining a cancer field. Engineered p16 tumor sufficiency is narrower than natural clonal-field independence." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "Register all five index subclaims. SC5 gates spontaneous mutation-independent epithelial initiation; engineered single-locus methylation, inflammatory induction, prediction and abnormal methylation presence are distinct. Age/exposure/genotype controls are antecedent, not responder-defined.", "primary_subclaim_id": "SC5", "aggregation_derivation": "The registered scope-matched gate SC5 gives Γ. SC2 and SC3 reach Ε in defined engineered or inflammatory settings, while SC1 and SC4 remain Β for causal inference from association. Weakest-link sensitivity is Β. Predictive value and causal contributions are retained without substituting for spontaneous independent field initiation.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Epigenetic predisposition cooperating with genetic and tissue-state events", "core_claim": "Methylation can alter fitness and tumor susceptibility while context and further changes determine malignancy.", "explains_what_nominal_does_not": "Methylation can alter fitness and tumor susceptibility while context and further changes determine malignancy.", "strongest_supporting_evidence": [ "Native p16 incidence, constitutional MLH1 predisposition, organoid Braf sensitization and Apc-p16 progression are complementary assay classes." ], "strongest_contradictory_evidence": [ "The p16 reports share one allele; natural epithelial field initiation and required cooperators are not universally resolved." ], "hsef_level_for_this_model": "Ζ", "rationale": "Native p16 incidence, constitutional MLH1 predisposition, organoid Braf sensitization and Apc-p16 progression are complementary assay classes. The p16 reports share one allele; natural epithelial field initiation and required cooperators are not universally resolved." }, { "rank_in_tournament": 2, "model_id": "M3", "is_nominal": false, "name": "Inflammatory induction with persistent epigenetic memory", "core_claim": "Inflammatory exposure generates partly durable methylation and alters tissue risk.", "explains_what_nominal_does_not": "Inflammatory exposure generates partly durable methylation and alters tissue risk.", "strongest_supporting_evidence": [ "Colonization-preserving inflammation suppression, withdrawal and exposure comparisons resolve simple bacterial-presence or proliferation explanations." ], "strongest_contradictory_evidence": [ "Global immune/repair changes and residual disease effects leave locus-specific cancer mediation incomplete." ], "hsef_level_for_this_model": "Ε", "rationale": "Colonization-preserving inflammation suppression, withdrawal and exposure comparisons resolve simple bacterial-presence or proliferation explanations. Global immune/repair changes and residual disease effects leave locus-specific cancer mediation incomplete." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Genetic initiation with epigenetic gatekeeping", "core_claim": "Selected driver clones can recruit methylation programs or exploit pre-existing epigenetic states.", "explains_what_nominal_does_not": "Selected driver clones can recruit methylation programs or exploit pre-existing epigenetic states.", "strongest_supporting_evidence": [ "KRAS-ZNF304 and BRAF-MAFG perturbations plus normal-tissue clonal sequencing show defined routes." ], "strongest_contradictory_evidence": [ "Tumor-cell results do not make all fields mutation-first; p16 and constitutional MLH1 prevent a categorical genetic-only claim." ], "hsef_level_for_this_model": "Ε", "rationale": "KRAS-ZNF304 and BRAF-MAFG perturbations plus normal-tissue clonal sequencing show defined routes. Tumor-cell results do not make all fields mutation-first; p16 and constitutional MLH1 prevent a categorical genetic-only claim." }, { "rank_in_tournament": 4, "model_id": "M1", "is_nominal": true, "name": "Spontaneous autonomous epigenetic cancer field", "core_claim": "Normal acquired methylation independently starts and sustains a clonal cancer field.", "explains_what_nominal_does_not": "Normal acquired methylation independently starts and sustains a clonal cancer field.", "strongest_supporting_evidence": [ "Crypt-level patterns and culture-associated Wnt/stemness changes provide mechanistic plausibility." ], "strongest_contradictory_evidence": [ "Prospective marker associations do not isolate clonal causality; native autonomous initiation lacks a positive scope-matched test." ], "hsef_level_for_this_model": "Γ", "rationale": "Crypt-level patterns and culture-associated Wnt/stemness changes provide mechanistic plausibility. Prospective marker associations do not isolate clonal causality; native autonomous initiation lacks a positive scope-matched test." }, { "rank_in_tournament": 5, "model_id": "M5", "is_nominal": false, "name": "Age and exposure-associated methylation drift", "core_claim": "Methylation records accumulated age/exposure and tissue state without necessarily driving every lesion.", "explains_what_nominal_does_not": "Methylation records accumulated age/exposure and tissue state without necessarily driving every lesion.", "strongest_supporting_evidence": [ "Strong age, inflammatory and organ-specific marker associations plus some normal-field nulls fit this model." ], "strongest_contradictory_evidence": [ "Engineered causal p16 and inflammatory DNMT interventions show that a pure passenger explanation is insufficient." ], "hsef_level_for_this_model": "Β", "rationale": "Strong age, inflammatory and organ-specific marker associations plus some normal-field nulls fit this model. Engineered causal p16 and inflammatory DNMT interventions show that a pure passenger explanation is insufficient." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Yu provides an engineered endogenous-locus incidence discriminator against a pure-passenger account; Tao and Yang distinguish autonomous initiation from context-dependent sensitization/progression. Prospective Asada and Yamada distinguish prediction from causality, while left-colon nulls delimit generalization.", "study_separating_rank1_from_rank2": "Yu provides an engineered endogenous-locus incidence discriminator against a pure-passenger account; Tao and Yang distinguish autonomous initiation from context-dependent sensitization/progression. Prospective Asada and Yamada distinguish prediction from causality, while left-colon nulls delimit generalization.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "31937549", "title": "DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia.", "citation": "Krishnan V, Lim DXE, Hoang PM et al. DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia. Gut. 2020.", "doi": "10.1136/gutjnl-2019-319002", "pmcid": "PMC7497583", "url": "https://pubmed.ncbi.nlm.nih.gov/31937549/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31937549/", "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": "PMID31937549", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human gastric intestinal metaplasia biopsies", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "DDR, mutation burden and repair-promoter methylation distinguish metaplastic states.", "what_it_does_not_show": "Cross-sectional DDR markers and methylation do not establish an independent initiating clone.", "confounders_present": [ "Cross-sectional DDR markers and methylation do not establish an independent initiating clone." ], "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": "25462860", "title": "Frequent involvement of chromatin remodeler alterations in gastric field cancerization.", "citation": "Takeshima H, Niwa T, Takahashi T et al. Frequent involvement of chromatin remodeler alterations in gastric field cancerization. Cancer letters. 2015.", "doi": "10.1016/j.canlet.2014.11.038", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25462860/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25462860/", "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": "PMID25462860", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human gastric tissue and cancer cell lines", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "SMARCA1/ACTL6B methylation occurs in noncancerous tissue; remodeler depletion promotes cancer-cell growth.", "what_it_does_not_show": "Mutation and methylation coexist; cancer-cell depletion does not reproduce spontaneous epithelial initiation.", "confounders_present": [ "Mutation and methylation coexist; cancer-cell depletion does not reproduce spontaneous epithelial 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": 3, "pmid": "37751933", "title": "Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation.", "citation": "Takeuchi C, Yamashita S, Liu YY et al. Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation. Gut. 2024.", "doi": "10.1136/gutjnl-2023-329492", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37751933/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37751933/", "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": "PMID37751933", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Isolated human IM crypts and inducible normal cells", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "IM has a distinctive methylome and NOS2 induction accelerates methylation.", "what_it_does_not_show": "An IM signature and artificial NOS2 induction do not show methylation alone initiates cancer.", "confounders_present": [ "An IM signature and artificial NOS2 induction do not show methylation alone initiates 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": 4, "pmid": "27992956", "title": "Degree of methylation burden is determined by the exposure period to carcinogenic factors.", "citation": "Takeshima H, Niwa T, Toyoda T et al. Degree of methylation burden is determined by the exposure period to carcinogenic factors. Cancer science. 2017.", "doi": "10.1111/cas.13136", "pmcid": "PMC5378290", "url": "https://pubmed.ncbi.nlm.nih.gov/27992956/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27992956/", "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": "Ushijima-gerbil-inflammation-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Gerbil gastritis exposure and withdrawal", "decisive_perturbation": true, "endogenous": true, "direction": "supporting", "what_it_shows": "Methylation burden increases with exposure and partly persists after withdrawal.", "what_it_does_not_show": "Persistence is not proof of autonomous cancer initiation; related gastric platform is grouped.", "confounders_present": [ "Persistence is not proof of autonomous cancer initiation; related gastric platform is grouped." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 5, "pmid": "22310288", "title": "DNA demethylation in normal colon tissue predicts predisposition to multiple cancers.", "citation": "Kamiyama H, Suzuki K, Maeda T et al. DNA demethylation in normal colon tissue predicts predisposition to multiple cancers. Oncogene. 2012.", "doi": "10.1038/onc.2011.652", "pmcid": "PMC4013778", "url": "https://pubmed.ncbi.nlm.nih.gov/22310288/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22310288/", "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": "PMID22310288", "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 normal colon and multiple cancer follow-up", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "LINE-1 hypomethylation associates with multiple cancers and predicts metachronous neoplasms.", "what_it_does_not_show": "This is hypomethylation, not the proposed promoter hypermethylation; observational prediction is not causation.", "confounders_present": [ "This is hypomethylation, not the proposed promoter hypermethylation; observational prediction is not causation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 6, "pmid": "16229808", "title": "Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis.", "citation": "Lee OJ, Schneider-Stock R, McChesney PA et al. Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis. Neoplasia (New York, N.Y.). 2005.", "doi": "10.1593/neo.05328", "pmcid": "PMC1501938", "url": "https://pubmed.ncbi.nlm.nih.gov/16229808/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16229808/", "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": "PMID16229808", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human Barrett progression samples", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "GPX3 promoter methylation rises through metaplasia, dysplasia and adenocarcinoma with reduced expression.", "what_it_does_not_show": "Stage association cannot resolve temporal initiation or independent clonal growth.", "confounders_present": [ "Stage association cannot resolve temporal initiation or independent clonal growth." ], "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": "33521965", "title": "Somatic mutation profiles as molecular classifiers of ulcerative colitis-associated colorectal cancer.", "citation": "Mäki-Nevala S, Ukwattage S, Olkinuora A et al. Somatic mutation profiles as molecular classifiers of ulcerative colitis-associated colorectal cancer. International journal of cancer. 2021.", "doi": "10.1002/ijc.33492", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33521965/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33521965/", "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": "PMID33521965", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human colitis-associated and Lynch colorectal cancers", "decisive_perturbation": false, "endogenous": false, "direction": "contradicting", "what_it_shows": "Genetic and epigenetic profiles identify distinct mutation-defined colitis cancer groups.", "what_it_does_not_show": "Tumor profiling is not a prospective test of normal methylated clone initiation.", "confounders_present": [ "Tumor profiling is not a prospective test of normal methylated clone 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": 8, "pmid": "26181641", "title": "Mosaic Epigenetic Inheritance as a Cause of Early-Onset Colorectal Cancer.", "citation": "Sloane MA, Nunez AC, Packham D et al. Mosaic Epigenetic Inheritance as a Cause of Early-Onset Colorectal Cancer. JAMA oncology. 2015.", "doi": "10.1001/jamaoncol.2015.1484", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26181641/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26181641/", "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": "PMID26181641", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Constitutional MLH1 epimutation family", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "A stable early-onset case inherited a constitutional epimutation from a mosaic asymptomatic mother without detected sequence alteration.", "what_it_does_not_show": "Rare constitutional predisposition differs from acquired epithelial field expansion; genomic absence remains bounded by detection.", "confounders_present": [ "Rare constitutional predisposition differs from acquired epithelial field expansion; genomic absence remains bounded by detection." ], "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": "31240997", "title": "DNA methyltransferase inhibition reduces inflammation-induced colon tumorigenesis.", "citation": "Maiuri AR, Savant SS, Podicheti R et al. DNA methyltransferase inhibition reduces inflammation-induced colon tumorigenesis. Epigenetics. 2019.", "doi": "10.1080/15592294.2019.1634986", "pmcid": "PMC6791707", "url": "https://pubmed.ncbi.nlm.nih.gov/31240997/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31240997/", "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": "O-Hagan-inflammatory-colon-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Murine inflammation-induced colon tumor model and tumoroids", "decisive_perturbation": true, "endogenous": true, "direction": "supporting", "what_it_shows": "DNMT inhibition reduces tumorigenesis and persistent inflammatory methylation; derived tumoroids differ in proliferation.", "what_it_does_not_show": "Broad drug effects, inflammatory context and shared precursor model prevent isolated spontaneous methylation sufficiency.", "confounders_present": [ "Broad drug effects, inflammatory context and shared precursor model prevent isolated spontaneous methylation sufficiency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Uses the inflammatory tumor model underlying PMID28522752." ] }, { "n": 10, "pmid": "23559452", "title": "Prevention of Helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent.", "citation": "Niwa T, Toyoda T, Tsukamoto T et al. Prevention of Helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent. Cancer prevention research (Philadelphia, Pa.). 2013.", "doi": "10.1158/1940-6207.CAPR-12-0369", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/23559452/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23559452/", "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": "PMID23559452", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Gerbil inflammation/carcinogen gastric cancer model", "decisive_perturbation": true, "endogenous": true, "direction": "supporting", "what_it_shows": "Demethylating treatment reduces cancer incidence with lower epithelial methylation.", "what_it_does_not_show": "Inflammatory cytokines also change and carcinogen exposure remains; no locus-specific mediation rescue or spontaneous field test.", "confounders_present": [ "Inflammatory cytokines also change and carcinogen exposure remains; no locus-specific mediation rescue or spontaneous field test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 11, "pmid": "25379950", "title": "Demonstration of the usefulness of epigenetic cancer risk prediction by a multicentre prospective cohort study.", "citation": "Asada K, Nakajima T, Shimazu T et al. Demonstration of the usefulness of epigenetic cancer risk prediction by a multicentre prospective cohort study. Gut. 2015.", "doi": "10.1136/gutjnl-2014-307094", "pmcid": "PMC4345890", "url": "https://pubmed.ncbi.nlm.nih.gov/25379950/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25379950/", "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": "PMID25379950", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Patients and methods, 2:Results. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Prospective multicentre post-resection gastric cohort", "decisive_perturbation": true, "endogenous": false, "direction": "supporting", "what_it_shows": "Preselected mucosal miR-124a-3 methylation predicts authentic later cancers with adjusted HR 2.30 and explicit early-event exclusion.", "what_it_does_not_show": "Three-year follow-up, modest events and residual confounding limit causality; not all marker or endpoint analyses are significant.", "confounders_present": [ "Three-year follow-up, modest events and residual confounding limit causality; not all marker or endpoint analyses are significant." ], "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": "38499886", "title": "Severe induction of aberrant DNA methylation by nodular gastritis in adults.", "citation": "Sasaki A, Takeshima H, Yamashita S et al. Severe induction of aberrant DNA methylation by nodular gastritis in adults. Journal of gastroenterology. 2024.", "doi": "10.1007/s00535-024-02094-y", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38499886/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38499886/", "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": "PMID38499886", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Age/sex-matched human nodular and atrophic gastritis", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Normal antral tissue in nodular gastritis has higher tumor-suppressor methylation, including in patients without cancer.", "what_it_does_not_show": "Small cross-sectional groups and tissue-state effects do not isolate inflammatory causation or initiation.", "confounders_present": [ "Small cross-sectional groups and tissue-state effects do not isolate inflammatory causation or initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 13, "pmid": "28522752", "title": "Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis.", "citation": "Maiuri AR, Peng M, Podicheti R et al. Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis. Cancer research. 2017.", "doi": "10.1158/0008-5472.CAN-17-0056", "pmcid": "PMC5516887", "url": "https://pubmed.ncbi.nlm.nih.gov/28522752/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28522752/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID29339372" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "O-Hagan-inflammatory-colon-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Murine inflammatory tumors with MSH2 perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "supporting", "what_it_shows": "MSH2 loss prevents early inflammation-associated epigenetic alterations and later hypermethylation.", "what_it_does_not_show": "MSH2 also affects repair and tumor biology; linked erratum body remains unexamined, limiting fine mechanistic certainty.", "confounders_present": [ "MSH2 also affects repair and tumor biology; linked erratum body remains unexamined, limiting fine mechanistic certainty." ], "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": "23292007", "title": "Altered mucosal DNA methylation in parallel with highly active Helicobacter pylori-related gastritis.", "citation": "Yoshida T, Kato J, Maekita T et al. Altered mucosal DNA methylation in parallel with highly active Helicobacter pylori-related gastritis. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2013.", "doi": "10.1007/s10120-012-0230-x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/23292007/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23292007/", "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": "PMID23292007", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human healthy-volunteer gastric biopsies", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Gastritis activity correlates with promoter gains and repeat losses of methylation.", "what_it_does_not_show": "Serological covariation is not an intervention or independent epimutation initiation.", "confounders_present": [ "Serological covariation is not an intervention or independent epimutation 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": 15, "pmid": "30443963", "title": "Antibiotics suppress colon tumorigenesis through inhibition of aberrant DNA methylation in an azoxymethane and dextran sulfate sodium colitis model.", "citation": "Hattori N, Niwa T, Ishida T et al. Antibiotics suppress colon tumorigenesis through inhibition of aberrant DNA methylation in an azoxymethane and dextran sulfate sodium colitis model. Cancer science. 2019.", "doi": "10.1111/cas.13880", "pmcid": "PMC6317928", "url": "https://pubmed.ncbi.nlm.nih.gov/30443963/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30443963/", "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": "PMID30443963", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Murine colitis/carcinogen model with antibiotics", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Antibiotics reduce inflammation, methylation markers and colon tumor burden together.", "what_it_does_not_show": "Multiple pathways change; methylation mediation is not isolated and the model is not spontaneous.", "confounders_present": [ "Multiple pathways change; methylation mediation is not isolated and the model is not spontaneous." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 16, "pmid": "19821005", "title": "Persistence of a component of DNA methylation in gastric mucosae after Helicobacter pylori eradication.", "citation": "Nakajima T, Enomoto S, Yamashita S et al. Persistence of a component of DNA methylation in gastric mucosae after Helicobacter pylori eradication. Journal of gastroenterology. 2010.", "doi": "10.1007/s00535-009-0142-7", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/19821005/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19821005/", "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": "PMID19821005", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Human longitudinal eradication biopsies", "decisive_perturbation": true, "endogenous": false, "direction": "supporting", "what_it_shows": "Successful eradication reduces marker methylation with marker-specific kinetics but leaves residual levels above uninfected controls.", "what_it_does_not_show": "Nonrandom intervention and cell-composition changes limit mediation; residual risk does not establish autonomous methylated clones.", "confounders_present": [ "Nonrandom intervention and cell-composition changes limit mediation; residual risk does not establish autonomous methylated clones." ], "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": "31645730", "title": "The landscape of somatic mutation in normal colorectal epithelial cells.", "citation": "Lee-Six H, Olafsson S, Ellis P et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature. 2019.", "doi": "10.1038/s41586-019-1672-7", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31645730/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31645730/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "normal-colon-WGS-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "Whole genomes of normal human colorectal crypts", "decisive_perturbation": true, "endogenous": false, "direction": "contradicting", "what_it_shows": "Probable drivers occur in about 1% of middle-age crypts; normal clonal evolution is genetically measurable.", "what_it_does_not_show": "Driver presence is not sufficient for cancer and epigenomes were not jointly measured; mutation-first is not universally proved.", "confounders_present": [ "Driver presence is not sufficient for cancer and epigenomes were not jointly measured; mutation-first is not universally proved." ], "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": "32697969", "title": "Somatic Evolution in Non-neoplastic IBD-Affected Colon.", "citation": "Olafsson S, McIntyre RE, Coorens T et al. Somatic Evolution in Non-neoplastic IBD-Affected Colon. Cell. 2020.", "doi": "10.1016/j.cell.2020.06.036", "pmcid": "PMC7427325", "url": "https://pubmed.ncbi.nlm.nih.gov/32697969/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32697969/", "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": "IBD-WGS-with-reused-control-crypts", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "Whole genomes of non-neoplastic IBD crypts", "decisive_perturbation": true, "endogenous": false, "direction": "contradicting", "what_it_shows": "IBD increases mutations and millimetre-scale clonal expansion with tissue-specific positive selection.", "what_it_does_not_show": "Control crypts reuse prior normal-colon publication; genetic selection does not exclude cooperative epigenetic effects.", "confounders_present": [ "Control crypts reuse prior normal-colon publication; genetic selection does not exclude cooperative epigenetic effects." ], "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": [ "Control crypts reuse prior normal-colon data from PMID31645730." ] }, { "n": 19, "pmid": "30337457", "title": "Somatic mutant clones colonize the human esophagus with age.", "citation": "Martincorena I, Fowler JC, Wabik A et al. Somatic mutant clones colonize the human esophagus with age. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aau3879", "pmcid": "PMC6298579", "url": "https://pubmed.ncbi.nlm.nih.gov/30337457/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30337457/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30337457", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "Normal human esophagus across age", "decisive_perturbation": true, "endogenous": false, "direction": "contradicting", "what_it_shows": "Normal epithelium becomes colonized by positively selected mutant clones, with NOTCH1 more prevalent than in cancers.", "what_it_does_not_show": "Cross-sectional clonal genetics does not show every clone is malignant or resolve methylation's additional contribution.", "confounders_present": [ "Cross-sectional clonal genetics does not show every clone is malignant or resolve methylation's additional contribution." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 20, "pmid": "31996850", "title": "Tobacco smoking and somatic mutations in human bronchial epithelium.", "citation": "Yoshida K, Gowers KHC, Lee-Six H et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature. 2020.", "doi": "10.1038/s41586-020-1961-1", "pmcid": "PMC7021511", "url": "https://pubmed.ncbi.nlm.nih.gov/31996850/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31996850/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31996850", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "Single-cell-derived normal bronchial colonies", "decisive_perturbation": true, "endogenous": false, "direction": "contradicting", "what_it_shows": "Smoking increases mutational burden and driver prevalence; cessation associates with less-mutated cells.", "what_it_does_not_show": "Colony culture and cross-sectional sampling constrain selection inference; no joint methylome lineage test.", "confounders_present": [ "Colony culture and cross-sectional sampling constrain selection inference; no joint methylome lineage test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "40108450", "title": "The somatic mutation landscape of normal gastric epithelium.", "citation": "Coorens THH, Collord G, Jung H et al. The somatic mutation landscape of normal gastric epithelium. Nature. 2025.", "doi": "10.1038/s41586-025-08708-6", "pmcid": "PMC11981919", "url": "https://pubmed.ncbi.nlm.nih.gov/40108450/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40108450/", "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": "PMID40108450", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:Driver mutations in gastric glands. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "Normal gastric glands, microdissections and targeted sequencing", "decisive_perturbation": true, "endogenous": false, "direction": "contradicting", "what_it_shows": "Distinct drivers and trisomies occur in normal glands; clone prevalence depends on age and inflammation, with normal/cancer CTNNB1 spectra differing.", "what_it_does_not_show": "Normal clones are not equivalent to cancer and methylation is not jointly perturbed; cancer-bearing donors contribute samples.", "confounders_present": [ "Normal clones are not equivalent to cancer and methylation is not jointly perturbed; cancer-bearing donors contribute samples." ], "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": "25999502", "title": "Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.", "citation": "Martincorena I, Roshan A, Gerstung M et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science (New York, N.Y.). 2015.", "doi": "10.1126/science.aaa6806", "pmcid": "PMC4471149", "url": "https://pubmed.ncbi.nlm.nih.gov/25999502/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25999502/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25999502", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "Normal sun-exposed skin sequencing", "decisive_perturbation": true, "endogenous": false, "direction": "contradicting", "what_it_shows": "Positive selection produces abundant cancer-gene mutant clones while tissue remains functional.", "what_it_does_not_show": "Four donors and targeted genes constrain coverage; genetic clone existence does not exclude epigenetic cooperation.", "confounders_present": [ "Four donors and targeted genes constrain coverage; genetic clone existence does not exclude epigenetic cooperation." ], "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": "27103033", "title": "Stochastic epigenetic outliers can define field defects in cancer.", "citation": "Teschendorff AE, Jones A, Widschwendter M. Stochastic epigenetic outliers can define field defects in cancer. BMC bioinformatics. 2016.", "doi": "10.1186/s12859-016-1056-z", "pmcid": "PMC4840974", "url": "https://pubmed.ncbi.nlm.nih.gov/27103033/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27103033/", "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": "PMID27103033", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "Reanalysis of over 700 primary methylomes", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Outlier-sensitive statistical approaches detect reproducible premalignant methylation field patterns.", "what_it_does_not_show": "Reused cohorts and algorithm comparisons are not independent causal interventions; biological selection is inferred.", "confounders_present": [ "Reused cohorts and algorithm comparisons are not independent causal interventions; biological selection is inferred." ], "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": "23555185", "title": "Methylation profiling defines an extensive field defect in histologically normal prostate tissues associated with prostate cancer.", "citation": "Yang B, Bhusari S, Kueck J et al. Methylation profiling defines an extensive field defect in histologically normal prostate tissues associated with prostate cancer. Neoplasia (New York, N.Y.). 2013.", "doi": "10.1593/neo.13280", "pmcid": "PMC3612912", "url": "https://pubmed.ncbi.nlm.nih.gov/23555185/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23555185/", "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": "PMID23555185", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human prostate spatial methylome profiling and validation", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "A widespread histologically normal prostate field profile validates beyond immediate tumor proximity.", "what_it_does_not_show": "Most altered loci are hypomethylated; cross-sectional tissue cannot establish initiation direction.", "confounders_present": [ "Most altered loci are hypomethylated; cross-sectional tissue cannot establish initiation 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": 25, "pmid": "18542073", "title": "Profiling CpG island field methylation in both morphologically normal and neoplastic human colonic mucosa.", "citation": "Belshaw NJ, Elliott GO, Foxall RJ et al. Profiling CpG island field methylation in both morphologically normal and neoplastic human colonic mucosa. British journal of cancer. 2008.", "doi": "10.1038/sj.bjc.6604432", "pmcid": "PMC2453007", "url": "https://pubmed.ncbi.nlm.nih.gov/18542073/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18542073/", "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": "PMID18542073", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "Normal human colon and neoplasia methylation profiling", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Age- and disease-associated CGI patterns discriminate normal mucosal groups.", "what_it_does_not_show": "Classifier accuracy within sampled groups does not demonstrate prospective risk or independent initiation.", "confounders_present": [ "Classifier accuracy within sampled groups does not demonstrate prospective risk or independent 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": 26, "pmid": "18058812", "title": "Quantitative, spatial resolution of the epigenetic field effect in prostate cancer.", "citation": "Mehrotra J, Varde S, Wang H et al. Quantitative, spatial resolution of the epigenetic field effect in prostate cancer. The Prostate. 2008.", "doi": "10.1002/pros.20675", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18058812/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18058812/", "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": "PMID18058812", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "Spatial human prostatectomy core series", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Field methylation is gene- and case-specific; GSTP1 field change is absent while some loci extend beyond tumor.", "what_it_does_not_show": "Small spatial sampling and occult-cell effects remain; lack of one marker is not absence of all fields.", "confounders_present": [ "Small spatial sampling and occult-cell effects remain; lack of one marker is not absence of all fields." ], "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": "15297416", "title": "Promoter hypermethylation of resected bronchial margins: a field defect of changes?", "citation": "Guo M, House MG, Hooker C et al. Promoter hypermethylation of resected bronchial margins: a field defect of changes? Clinical cancer research : an official journal of the American Association for Cancer Research. 2004.", "doi": "10.1158/1078-0432.CCR-03-0763", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15297416/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15297416/", "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": "PMID15297416", "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": "Resected bronchial margins and recurrence follow-up", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Histologically negative margins often share tumor methylation but no significant recurrence correlation is found.", "what_it_does_not_show": "Twenty patients and few recurrences limit power; negative margins do not prove independent normal clones.", "confounders_present": [ "Twenty patients and few recurrences limit power; negative margins do not prove independent normal clones." ], "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": "25638164", "title": "Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans.", "citation": "Alonso S, Dai Y, Yamashita K et al. Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans. Oncotarget. 2015.", "doi": "10.18632/oncotarget.2852", "pmcid": "PMC4413663", "url": "https://pubmed.ncbi.nlm.nih.gov/25638164/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25638164/", "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": "PMID25638164", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human CRC, normal mucosa, exomes and TCGA", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "MGMT/ADAMTS14 normal-mucosal fields correlate with age, but MGMT methylation has no significant KRAS/TP53 or exome G-to-A association.", "what_it_does_not_show": "Null mutation association does not rule out other methylation consequences; cross-sectional ancestry associations are not causal mechanisms.", "confounders_present": [ "Null mutation association does not rule out other methylation consequences; cross-sectional ancestry associations are not causal mechanisms." ], "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": "26792292", "title": "Epigenetic inactivation of FAT4 contributes to gastric field cancerization.", "citation": "Yoshida S, Yamashita S, Niwa T et al. Epigenetic inactivation of FAT4 contributes to gastric field cancerization. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2017.", "doi": "10.1007/s10120-016-0593-5", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26792292/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26792292/", "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": "PMID26792292", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human gastric tissue and cell-line demethylation", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "FAT4 methylation silences expression and is associated with infection and cancer in noncancerous mucosa.", "what_it_does_not_show": "Broad demethylation restores expression without demonstrating native field initiation or incidence.", "confounders_present": [ "Broad demethylation restores expression without demonstrating native field initiation or incidence." ], "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": "23867875", "title": "Methylated eyes absent 4 (EYA4) gene promotor in non-neoplastic mucosa of ulcerative colitis patients with colorectal cancer: evidence for a field effect.", "citation": "Kisiel JB, Garrity-Park MM, Taylor WR et al. Methylated eyes absent 4 (EYA4) gene promotor in non-neoplastic mucosa of ulcerative colitis patients with colorectal cancer: evidence for a field effect. Inflammatory bowel diseases. 2013.", "doi": "10.1097/MIB.0b013e31829b3f4d", "pmcid": "PMC4119944", "url": "https://pubmed.ncbi.nlm.nih.gov/23867875/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23867875/", "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": "PMID23867875", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "Matched UC cases/controls and non-neoplastic mucosa", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "EYA4 methylation is elevated beyond the tumor in UC cases with synchronous CRC.", "what_it_does_not_show": "Synchronous case-control signal, wide odds-ratio uncertainty and incomplete tissue availability limit prospective inference.", "confounders_present": [ "Synchronous case-control signal, wide odds-ratio uncertainty and incomplete tissue availability limit prospective 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": 31, "pmid": "20947886", "title": "Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers.", "citation": "Svrcek M, Buhard O, Colas C et al. Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers. Gut. 2010.", "doi": "10.1136/gut.2009.194787", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20947886/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20947886/", "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": "PMID20947886", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Familial, sporadic and IBD CRC with spatial mucosa", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "MGMT-deficient mucosal patches associate more often with MSI cancers.", "what_it_does_not_show": "The proposed ordering from MGMT loss to MMR deficiency is inferred, not traced prospectively or selectively rescued.", "confounders_present": [ "The proposed ordering from MGMT loss to MMR deficiency is inferred, not traced prospectively or selectively rescued." ], "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": "32255732", "title": "Enrichment of CpG island shore region hypermethylation in epigenetic breast field cancerization.", "citation": "Muse ME, Titus AJ, Salas LA et al. Enrichment of CpG island shore region hypermethylation in epigenetic breast field cancerization. Epigenetics. 2020.", "doi": "10.1080/15592294.2020.1747748", "pmcid": "PMC7518670", "url": "https://pubmed.ncbi.nlm.nih.gov/32255732/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32255732/", "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": "PMID32255732", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "Laser-captured bilateral normal breast and matched tumors", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Ipsilateral normal breast shows CGI-shore changes relative to contralateral epithelium.", "what_it_does_not_show": "Nine cancer-bearing women; contralateral tissue is not a cancer-free population and spatial ordering is not temporal causality.", "confounders_present": [ "Nine cancer-bearing women; contralateral tissue is not a cancer-free population and spatial ordering is not temporal causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "25859284", "title": "LINE-1 hypomethylation is neither present in rectal aberrant crypt foci nor associated with field defect in sporadic colorectal neoplasia.", "citation": "Quintanilla I, Lopez-Cerón M, Jimeno M et al. LINE-1 hypomethylation is neither present in rectal aberrant crypt foci nor associated with field defect in sporadic colorectal neoplasia. Clinical epigenetics. 2014.", "doi": "10.1186/1868-7083-6-24", "pmcid": "PMC4391726", "url": "https://pubmed.ncbi.nlm.nih.gov/25859284/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25859284/", "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": "PMID25859284", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "Rectal ACF and normal colorectal tissue with controls", "decisive_perturbation": true, "endogenous": false, "direction": "null", "what_it_shows": "LINE-1 field hypomethylation is absent; segment-specific methylation differences are detected.", "what_it_does_not_show": "This negative result addresses repeat methylation, not every promoter field; rectal ACF differ from right-colon adenomas.", "confounders_present": [ "This negative result addresses repeat methylation, not every promoter field; rectal ACF differ from right-colon adenomas." ], "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": "20924086", "title": "Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect.", "citation": "Suzuki H, Yamamoto E, Nojima M et al. Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect. Carcinogenesis. 2010.", "doi": "10.1093/carcin/bgq203", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20924086/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20924086/", "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": "PMID20924086", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human gastric fields and cancer-cell miRNA restoration", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "miR-34b/c methylation tracks multiple gastric cancer and restoration suppresses cancer-cell growth.", "what_it_does_not_show": "Synthetic RNA restoration in cancer cells does not isolate spontaneous field initiation in vivo.", "confounders_present": [ "Synthetic RNA restoration in cancer cells does not isolate spontaneous field initiation 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": [] }, { "n": 35, "pmid": "29427040", "title": "Novel epigenetic markers for gastric cancer risk stratification in individuals after Helicobacter pylori eradication.", "citation": "Maeda M, Yamashita S, Shimazu T et al. Novel epigenetic markers for gastric cancer risk stratification in individuals after Helicobacter pylori eradication. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2018.", "doi": "10.1007/s10120-018-0803-4", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29427040/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29427040/", "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": "PMID29427040", "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": "Post-eradication gastric discovery/validation samples", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "New correlated mucosal methylation markers discriminate gastric cancer from atrophic controls.", "what_it_does_not_show": "Case-control discrimination is not prospective incidence; shared exposure and marker covariance remain.", "confounders_present": [ "Case-control discrimination is not prospective incidence; shared exposure and marker covariance 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": 36, "pmid": "29358395", "title": "Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues.", "citation": "Yamashita S, Kishino T, Takahashi T et al. Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues. Proceedings of the National Academy of Sciences of the United States of America. 2018.", "doi": "10.1073/pnas.1717340115", "pmcid": "PMC5819434", "url": "https://pubmed.ncbi.nlm.nih.gov/29358395/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29358395/", "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": "PMID29358395", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human normal esophageal and gastric risk-group comparison", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Relative predictive contribution of genetic and epigenetic alterations differs by tissue.", "what_it_does_not_show": "Risk groups are defined partly by existing cancer; targeted mutation assays do not establish epigenetic independence.", "confounders_present": [ "Risk groups are defined partly by existing cancer; targeted mutation assays do not establish epigenetic independence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 37, "pmid": "19450526", "title": "Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary.", "citation": "Witcher M, Emerson BM. Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary. Molecular cell. 2009.", "doi": "10.1016/j.molcel.2009.04.001", "pmcid": "PMC2723750", "url": "https://pubmed.ncbi.nlm.nih.gov/19450526/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19450526/", "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": "PMID19450526", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Cancer-cell chromatin boundary and binding assays", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "p16 silencing associates with CTCF boundary loss and altered protein regulation.", "what_it_does_not_show": "Established cancer cells and correlated chromatin changes do not identify spontaneous normal epithelial field initiation.", "confounders_present": [ "Established cancer cells and correlated chromatin changes do not identify spontaneous normal epithelial field 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": 38, "pmid": "25866970", "title": "TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts.", "citation": "Bernstein DL, Le Lay JE, Ruano EG et al. TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts. The Journal of clinical investigation. 2015.", "doi": "10.1172/JCI77321", "pmcid": "PMC4463192", "url": "https://pubmed.ncbi.nlm.nih.gov/25866970/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25866970/", "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": "PMID25866970", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "Targeted methylation of primary human fibroblasts with p16 rescue", "decisive_perturbation": true, "endogenous": false, "direction": "supporting", "what_it_shows": "Locus-directed suppression increases replication and p16 restoration reverses the phenotype.", "what_it_does_not_show": "Fibroblast replication is not epithelial malignancy or spontaneous in-vivo incidence; engineered delivery defines scope.", "confounders_present": [ "Fibroblast replication is not epithelial malignancy or spontaneous in-vivo incidence; engineered delivery defines scope." ], "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": "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": "Shen-p16-cis-lineage", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 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": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "Endogenous p16 cis-element knock-in mice", "decisive_perturbation": true, "endogenous": true, "direction": "supporting", "what_it_shows": "Engineered promoter methylation represses p16 and raises spontaneous tumor incidence without a required engineered oncogene; inserted-sequence controls and expression restoration support mechanism.", "what_it_does_not_show": "The initiating allele is engineered DNA; mixed backgrounds, small tumor cohorts, non-epithelial tumor spectrum and absent whole-genome lineage/rescue constrain natural-field transfer.", "confounders_present": [ "The initiating allele is engineered DNA; mixed backgrounds, small tumor cohorts, non-epithelial tumor spectrum and absent whole-genome lineage/rescue constrain natural-field transfer." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": true, "supporting_count": 1, "mentioning_count": 71, "contrasting_count": 0, "notable_contrasting_statements": [], "note": "Provider-indexed aggregate citation counts and selected outgoing references, not an incoming contradiction-body audit or quality score." }, "shared_components": [] }, { "n": 40, "pmid": "24623306", "title": "A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype.", "citation": "Serra RW, Fang M, Park SM et al. A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype. eLife. 2014.", "doi": "10.7554/eLife.02313", "pmcid": "PMC3949416", "url": "https://pubmed.ncbi.nlm.nih.gov/24623306/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24623306/", "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": "PMID24623306", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "KRAS-positive human CRC cells and tumors", "decisive_perturbation": true, "endogenous": false, "direction": "contradicting", "what_it_shows": "KRAS-linked ZNF304 recruitment mediates DNMT1-associated CIMP silencing.", "what_it_does_not_show": "Cancer-cell dependency is not universal mutation-first initiation; related RNAi platform is grouped.", "confounders_present": [ "Cancer-cell dependency is not universal mutation-first initiation; related RNAi platform is grouped." ], "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": "26787892", "title": "Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma.", "citation": "Fang M, Hutchinson L, Deng A et al. Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma. Proceedings of the National Academy of Sciences of the United States of America. 2016.", "doi": "10.1073/pnas.1525619113", "pmcid": "PMC4747705", "url": "https://pubmed.ncbi.nlm.nih.gov/26787892/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26787892/", "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": "Green-MAFG-pathway", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "BRAF-positive CRC and melanoma cell models", "decisive_perturbation": true, "endogenous": false, "direction": "contradicting", "what_it_shows": "BRAF-MAFG corepressor pathway directs methylation-linked silencing in two cancer settings.", "what_it_does_not_show": "Shares pathway/platform with earlier CRC report; no proof that all natural methylation fields originate genetically.", "confounders_present": [ "Shares pathway/platform with earlier CRC report; no proof that all natural methylation fields originate genetically." ], "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": "30753828", "title": "Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and BrafV600E-Induced Tumorigenesis.", "citation": "Tao Y, Kang B, Petkovich DA et al. Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and BrafV600E-Induced Tumorigenesis. Cancer cell. 2019.", "doi": "10.1016/j.ccell.2019.01.005", "pmcid": "PMC6636642", "url": "https://pubmed.ncbi.nlm.nih.gov/30753828/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30753828/", "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": "PMID30753828", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph8, 1:RESULTS:paragraph11, 1:RESULTS:paragraph12, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph15, 1:RESULTS:paragraph16, 1:RESULTS:paragraph17. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "Long-cultured mouse colon organoids, gene deletions and xenografts", "decisive_perturbation": true, "endogenous": false, "direction": "supporting", "what_it_shows": "Spontaneous culture-associated methylation creates Wnt/stemness changes and sharply accelerates Braf-dependent transformation.", "what_it_does_not_show": "Culture aging is not chronological native epithelium; Braf is required in the tested transformation comparison and some selected outgrowths acquire Wnt mutations.", "confounders_present": [ "Culture aging is not chronological native epithelium; Braf is required in the tested transformation comparison and some selected outgrowths acquire Wnt mutations." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": true, "supporting_count": 9, "mentioning_count": 160, "contrasting_count": 0, "notable_contrasting_statements": [], "note": "Provider-indexed aggregate citation counts and selected outgoing references, not an incoming contradiction-body audit or quality score." }, "shared_components": [] }, { "n": 43, "pmid": "25219500", "title": "The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype.", "citation": "Fang M, Ou J, Hutchinson L et al. The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype. Molecular cell. 2014.", "doi": "10.1016/j.molcel.2014.08.010", "pmcid": "PMC4170521", "url": "https://pubmed.ncbi.nlm.nih.gov/25219500/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25219500/", "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": "Green-MAFG-pathway", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "BRAF-positive human CRC RNAi and chromatin assays", "decisive_perturbation": true, "endogenous": false, "direction": "contradicting", "what_it_shows": "MAFG depletion resolves an oncogene-directed MLH1/CIMP repression pathway.", "what_it_does_not_show": "Related study line and established tumor cells limit initiation transfer; does not erase epigenetic-first sensitization.", "confounders_present": [ "Related study line and established tumor cells limit initiation transfer; does not erase epigenetic-first sensitization." ], "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": "15064764", "title": "Germline epimutation of MLH1 in individuals with multiple cancers.", "citation": "Suter CM, Martin DI, Ward RL. Germline epimutation of MLH1 in individuals with multiple cancers. Nature genetics. 2004.", "doi": "10.1038/ng1342", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15064764/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15064764/", "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": "PMID15064764", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Two human constitutional MLH1 epimutation cases", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Soma-wide allele-specific MLH1 methylation accompanies multiple mismatch-repair-deficient tumors without detected MMR mutation.", "what_it_does_not_show": "Rare constitutional predisposition and bounded mutation detection do not establish common acquired epithelial field expansion.", "confounders_present": [ "Rare constitutional predisposition and bounded mutation detection do not establish common acquired epithelial field expansion." ], "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": "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": "PMID30283143", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Twelve constitutional MLH1 carriers with controls and molecular characterization", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Ten carriers lack detected cis nucleotide/structural variants; the focal methylation event can erase across generations.", "what_it_does_not_show": "Other CNVs in two cases and unsolved mechanism constrain pure epigenetic independence; rare constitutional scope remains.", "confounders_present": [ "Other CNVs in two cases and unsolved mechanism constrain pure epigenetic independence; rare constitutional scope remains." ], "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": "28304185", "title": "Modulation of transcription factor binding and epigenetic regulation of the MLH1 CpG island and shore by polymorphism rs1800734 in colorectal cancer.", "citation": "Savio AJ, Bapat B. Modulation of transcription factor binding and epigenetic regulation of the MLH1 CpG island and shore by polymorphism rs1800734 in colorectal cancer. Epigenetics. 2017.", "doi": "10.1080/15592294.2017.1305527", "pmcid": "PMC5501216", "url": "https://pubmed.ncbi.nlm.nih.gov/28304185/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28304185/", "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": "PMID28304185", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Genotype-stratified CRC lines and allele-specific binding", "decisive_perturbation": false, "endogenous": false, "direction": "contradicting", "what_it_shows": "MLH1 promoter genotype alters AP4 binding and shore methylation.", "what_it_does_not_show": "Local genetic regulation need not explain all MLH1 epimutations or spontaneous field clones.", "confounders_present": [ "Local genetic regulation need not explain all MLH1 epimutations or spontaneous field clones." ], "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": "26823093", "title": "DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer.", "citation": "Teschendorff AE, Gao Y, Jones A et al. DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer. Nature communications. 2016.", "doi": "10.1038/ncomms10478", "pmcid": "PMC4740178", "url": "https://pubmed.ncbi.nlm.nih.gov/26823093/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26823093/", "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": "PMID26823093", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "Normal breast methylomes with independent cohort validation", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Outlier fields enrich architecture-factor loci and progress in paired cancer samples.", "what_it_does_not_show": "Computational cellular-mixture adjustment and cross-sectional tissue cannot establish clonal causality; related outlier algorithms share assumptions.", "confounders_present": [ "Computational cellular-mixture adjustment and cross-sectional tissue cannot establish clonal causality; related outlier algorithms share assumptions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "37219707", "title": "The methylation level of a single cancer risk marker gene reflects methylation burden in gastric mucosa.", "citation": "Irie T, Yamada H, Takeuchi C et al. The methylation level of a single cancer risk marker gene reflects methylation burden in gastric mucosa. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2023.", "doi": "10.1007/s10120-023-01399-w", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37219707/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37219707/", "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": "PMID37219707", "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": "Post-eradication gastric methylome and marker comparison", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Single-marker methylation correlates with genome-wide burden and candidate driver methylation.", "what_it_does_not_show": "Biomarker covariance is not mediation or independent initiation; discovery and validation sample roles differ.", "confounders_present": [ "Biomarker covariance is not mediation or independent initiation; discovery and validation sample roles differ." ], "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": "37143122", "title": "Functional characterization of age-dependent p16 epimutation reveals biological drivers and therapeutic targets for colorectal cancer.", "citation": "Yang L, Chen X, Lee C et al. Functional characterization of age-dependent p16 epimutation reveals biological drivers and therapeutic targets for colorectal cancer. Journal of experimental & clinical cancer research : CR. 2023.", "doi": "10.1186/s13046-023-02689-y", "pmcid": "PMC10157929", "url": "https://pubmed.ncbi.nlm.nih.gov/37143122/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37143122/", "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": "Shen-p16-cis-lineage", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph2, 2:Results:paragraph3, 2:Results:paragraph5, 2:Results:paragraph17. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "p16 epimutation/Apc mouse model and tumor organoids", "decisive_perturbation": true, "endogenous": true, "direction": "supporting", "what_it_shows": "p16 epimutation cooperates with Apc, changes immune milieu and tumor progression; targeted demethylation restores p16 in fibroblasts.", "what_it_does_not_show": "Shared cis-element lineage with Yu; tumors arise in Apc-mutant context and broad drug/immune effects prevent autonomous initiation inference.", "confounders_present": [ "Shared cis-element lineage with Yu; tumors arise in Apc-mutant context and broad drug/immune effects prevent autonomous initiation 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": [ "Uses the engineered p16 cis-element lineage from PMID25061879; new Apc and immune context, not independent allele replication." ] }, { "n": 50, "pmid": "16467114", "title": "High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk.", "citation": "Maekita T, Nakazawa K, Mihara M et al. High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006.", "doi": "10.1158/1078-0432.CCR-05-2096", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16467114/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16467114/", "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": "PMID16467114", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Human normal gastric mucosa with infection/cancer stratification", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Methylation is strongly associated with infection and, after exposure stratification, with existing cancer.", "what_it_does_not_show": "Cross-sectional exposure signal and variability are not independent epigenetic initiation.", "confounders_present": [ "Cross-sectional exposure signal and variability are not independent epigenetic 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": 51, "pmid": "17119066", "title": "Higher methylation levels in gastric mucosae significantly correlate with higher risk of gastric cancers.", "citation": "Nakajima T, Maekita T, Oda I et al. Higher methylation levels in gastric mucosae significantly correlate with higher risk of gastric cancers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2006.", "doi": "10.1158/1055-9965.EPI-06-0436", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17119066/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17119066/", "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": "PMID17119066", "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 healthy, single and multiple gastric cancer groups", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Post-infection marker methylation increases across cancer-risk groups after atrophy adjustment.", "what_it_does_not_show": "Existing multiple cancers define risk groups; association does not trace or perturb a field clone.", "confounders_present": [ "Existing multiple cancers define risk groups; association does not trace or perturb a field clone." ], "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": "35939560", "title": "Long-term changes in aberrant DNA methylation and gastritis after Helicobacter pylori eradication focused on metachronous gastric cancer.", "citation": "Tanaka I, Ono S, Watanabe Y et al. Long-term changes in aberrant DNA methylation and gastritis after Helicobacter pylori eradication focused on metachronous gastric cancer. Helicobacter. 2022.", "doi": "10.1111/hel.12915", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35939560/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35939560/", "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": "PMID35939560", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Longitudinal gastric biopsies classified by later cancer", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Marker methylation improves after eradication in some groups but persists with metachronous cancer.", "what_it_does_not_show": "Outcome-selected groups and limited sample sizes are not a preregistered independent causal test.", "confounders_present": [ "Outcome-selected groups and limited sample sizes are not a preregistered independent causal test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "23942619", "title": "Aberrant methylation of microRNA-34b/c is a predictive marker of metachronous gastric cancer risk.", "citation": "Suzuki R, Yamamoto E, Nojima M et al. Aberrant methylation of microRNA-34b/c is a predictive marker of metachronous gastric cancer risk. Journal of gastroenterology. 2014.", "doi": "10.1007/s00535-013-0861-7", "pmcid": "PMC4083150", "url": "https://pubmed.ncbi.nlm.nih.gov/23942619/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23942619/", "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": "PMID23942619", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Scheduled prospective follow-up after gastric resection", "decisive_perturbation": true, "endogenous": false, "direction": "supporting", "what_it_shows": "Baseline miR-34b/c predicts later cancer after covariate adjustment in 129 patients.", "what_it_does_not_show": "Seventeen events and observational tissue markers do not establish independent methylation-driven initiation.", "confounders_present": [ "Seventeen events and observational tissue markers do not establish independent methylation-driven 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": 54, "pmid": "35038821", "title": "Aberrant DNA Methylation Maker for Predicting Metachronous Recurrence After Endoscopic Resection of Gastric Neoplasms.", "citation": "Shin CM, Kim N, Yoon H et al. Aberrant DNA Methylation Maker for Predicting Metachronous Recurrence After Endoscopic Resection of Gastric Neoplasms. Cancer research and treatment. 2022.", "doi": "10.4143/crt.2021.997", "pmcid": "PMC9582476", "url": "https://pubmed.ncbi.nlm.nih.gov/35038821/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35038821/", "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": "PMID35038821", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Prospectively enrolled post-resection gastric neoplasia cohort", "decisive_perturbation": true, "endogenous": false, "direction": "supporting", "what_it_shows": "Baseline MOS predicts later metachronous neoplasms with adjusted HR 4.76.", "what_it_does_not_show": "Only 124 of 294 completed the protocol; outcome mixes adenomas and seven cancers and threshold requires external validation.", "confounders_present": [ "Only 124 of 294 completed the protocol; outcome mixes adenomas and seven cancers and threshold requires external validation." ], "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": "27557505", "title": "A polycomb-mediated epigenetic field defect precedes invasive cervical carcinoma.", "citation": "Wijetunga NA, Ben-Dayan M, Tozour J et al. A polycomb-mediated epigenetic field defect precedes invasive cervical carcinoma. Oncotarget. 2016.", "doi": "10.18632/oncotarget.11390", "pmcid": "PMC5308716", "url": "https://pubmed.ncbi.nlm.nih.gov/27557505/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27557505/", "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": "PMID27557505", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "HPV-positive cervical neoplasia stages and external validation", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Early polycomb-target methylation and local expression changes persist through progression.", "what_it_does_not_show": "Stage ordering is not prospective clonal tracing; HPV context precludes autonomous epigenetic initiation inference.", "confounders_present": [ "Stage ordering is not prospective clonal tracing; HPV context precludes autonomous epigenetic initiation 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": 56, "pmid": "36219239", "title": "Epigenome-Wide Study Identifies Epigenetic Outliers in Normal Mucosa of Patients with Colorectal Cancer.", "citation": "Ghosh J, Schultz BM, Chan J et al. Epigenome-Wide Study Identifies Epigenetic Outliers in Normal Mucosa of Patients with Colorectal Cancer. Cancer prevention research (Philadelphia, Pa.). 2022.", "doi": "10.1158/1940-6207.CAPR-22-0258", "pmcid": "PMC9623234", "url": "https://pubmed.ncbi.nlm.nih.gov/36219239/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36219239/", "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": "PMID36219239", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "Normal CRC mucosa, controls, expression and microbiome profiles", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Outlier methylation phenotype occurs in 15/77 CRC cases versus 0/68 controls with transcriptional changes.", "what_it_does_not_show": "Case-control OMP signal is not prospective incidence or proof of microbial or methylation causal ordering.", "confounders_present": [ "Case-control OMP signal is not prospective incidence or proof of microbial or methylation causal ordering." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "38273663", "title": "DNA-methylation variability in normal mucosa: a field cancerization marker in patients with adenomatous polyps.", "citation": "Yates J, Schaufelberger H, Steinacher R et al. DNA-methylation variability in normal mucosa: a field cancerization marker in patients with adenomatous polyps. Journal of the National Cancer Institute. 2024.", "doi": "10.1093/jnci/djae016", "pmcid": "PMC11160500", "url": "https://pubmed.ncbi.nlm.nih.gov/38273663/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38273663/", "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": "PMID38273663", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph4, 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph10, 1:Results:paragraph14, 1:Results:paragraph15. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "SWEPIC normal cecal biopsies and external classifier validation", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "558 loci distinguish adenoma-adjacent mucosa, with external validation and age/cell-composition checks.", "what_it_does_not_show": "AUC is cross-sectional classification, not prediction of subsequent incident cancer; many loci associate with age.", "confounders_present": [ "AUC is cross-sectional classification, not prediction of subsequent incident cancer; many loci associate with age." ], "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": "20395289", "title": "Patterns of DNA methylation in individual colonic crypts reveal aging and cancer-related field defects in the morphologically normal mucosa.", "citation": "Belshaw NJ, Pal N, Tapp HS et al. Patterns of DNA methylation in individual colonic crypts reveal aging and cancer-related field defects in the morphologically normal mucosa. Carcinogenesis. 2010.", "doi": "10.1093/carcin/bgq077", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20395289/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20395289/", "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": "PMID20395289", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "260 individual human colon crypts from thirteen women", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Crypt methylation varies within donors and associates with age/disease, with all-or-none CGI patterns.", "what_it_does_not_show": "Clonal units are sampled cross-sectionally without genome/epigenome fate tracking; combined mutation mechanism is proposed.", "confounders_present": [ "Clonal units are sampled cross-sectionally without genome/epigenome fate tracking; combined mutation mechanism is proposed." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "28540987", "title": "Lack of Aberrant Methylation in an Adjacent Area of Left-Sided Colorectal Cancer.", "citation": "Sambuudash O, Kim HS, Cho MY. Lack of Aberrant Methylation in an Adjacent Area of Left-Sided Colorectal Cancer. Yonsei medical journal. 2017.", "doi": "10.3349/ymj.2017.58.4.749", "pmcid": "PMC5447105", "url": "https://pubmed.ncbi.nlm.nih.gov/28540987/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28540987/", "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": "PMID28540987", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:RESULTS. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "Age/sex-matched left-colon cancers, adjacent tissue and controls", "decisive_perturbation": true, "endogenous": false, "direction": "null", "what_it_shows": "Most candidate methylation fields are absent despite strong tumor signals; adjacent hotspots are negative.", "what_it_does_not_show": "Candidate panel and modest cohort cannot exclude every epimutation; abstract/body single-locus estimates differ and are not pooled.", "confounders_present": [ "Candidate panel and modest cohort cannot exclude every epimutation; abstract/body single-locus estimates differ and are not pooled." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 60, "pmid": "20124475", "title": "Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells.", "citation": "Niwa T, Tsukamoto T, Toyoda T et al. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer research. 2010.", "doi": "10.1158/0008-5472.CAN-09-2755", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20124475/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20124475/", "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": "Ushijima-gerbil-inflammation-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Gerbil inflammation suppression and withdrawal", "decisive_perturbation": true, "endogenous": true, "direction": "supporting", "what_it_shows": "Suppressing inflammation leaves bacterial colonization intact but blocks methylation induction; withdrawal leaves a residual component.", "what_it_does_not_show": "Broad immunosuppression and exposure-defined tissue do not isolate autonomous methylation-mediated cancer initiation.", "confounders_present": [ "Broad immunosuppression and exposure-defined tissue do not isolate autonomous methylation-mediated cancer initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 61, "pmid": "16174854", "title": "MGMT promoter methylation and field defect in sporadic colorectal cancer.", "citation": "Shen L, Kondo Y, Rosner GL et al. MGMT promoter methylation and field defect in sporadic colorectal cancer. Journal of the National Cancer Institute. 2005.", "doi": "10.1093/jnci/dji275", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16174854/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16174854/", "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": "PMID16174854", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "Spatial human colon methylation assays and KRAS analysis", "decisive_perturbation": false, "endogenous": false, "direction": "supporting", "what_it_shows": "Multiple assays detect MGMT fields well beyond tumors and associate tumor methylation with KRAS transitions.", "what_it_does_not_show": "Normal-mucosal mutation association is nonsignificant; ordering and clonal fitness are not directly tested.", "confounders_present": [ "Normal-mucosal mutation association is nonsignificant; ordering and clonal fitness are not directly tested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 62, "pmid": "20980348", "title": "Insufficient role of cell proliferation in aberrant DNA methylation induction and involvement of specific types of inflammation.", "citation": "Hur K, Niwa T, Toyoda T et al. Insufficient role of cell proliferation in aberrant DNA methylation induction and involvement of specific types of inflammation. Carcinogenesis. 2011.", "doi": "10.1093/carcin/bgq219", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20980348/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20980348/", "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": "Ushijima-gerbil-inflammation-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Contrasting gastric inflammatory states in gerbils", "decisive_perturbation": true, "endogenous": true, "direction": "supporting", "what_it_shows": "Strong proliferation alone fails to induce the same methylation; inflammatory type matters.", "what_it_does_not_show": "Related gastric platform and different exposures limit independent replication; outcome is methylation rather than cancer incidence.", "confounders_present": [ "Related gastric platform and different exposures limit independent replication; outcome is methylation rather than cancer incidence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 63, "pmid": "40240063", "title": "Precision risk stratification of primary gastric cancer after eradication of H. pylori by a DNA methylation marker: a multicentre prospective study.", "citation": "Yamada H, Abe S, Charvat H et al. Precision risk stratification of primary gastric cancer after eradication of H. pylori by a DNA methylation marker: a multicentre prospective study. Gut. 2025.", "doi": "10.1136/gutjnl-2025-335039", "pmcid": "PMC12418579", "url": "https://pubmed.ncbi.nlm.nih.gov/40240063/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40240063/", "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": "PMID40240063", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "Independent prospective primary gastric cancer cohort after eradication", "decisive_perturbation": true, "endogenous": false, "direction": "supporting", "what_it_shows": "1624 followed participants with 27 incident cancers validate RIMS1 risk gradients with adjusted HR 5.7.", "what_it_does_not_show": "Wide interval and atrophy-selected population constrain transfer; marker burden validation uses separate archived samples, and methylation is not experimentally altered.", "confounders_present": [ "Wide interval and atrophy-selected population constrain transfer; marker burden validation uses separate archived samples, and methylation is not experimentally altered." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": true, "supporting_count": 0, "mentioning_count": 11, "contrasting_count": 0, "notable_contrasting_statements": [], "note": "Provider-indexed aggregate citation counts and selected outgoing references, not an incoming contradiction-body audit or quality score." }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 69, "verified": 69, "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": "Normal epithelial methylation fields are reproducible, spatially measurable and often associated with neoplasia. This is robust existence/association evidence, with locus and organ-specific nulls; the Β cancer-association cap does not deny their existence.", "resulting_ceiling": "Β" }, { "subclaim_id": "SC4", "cap": "Β", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "**Association-only cancer claims cap at Β.**", "specific_trigger": "Several prospective cohorts demonstrate later cancer or neoplasia associations, including independent primary-incidence and metachronous cohorts. The Β association cap applies to causal interpretation, not to the validated predictive signal. Marker alteration has not itself been selectively shown to change human incidence.", "resulting_ceiling": "Β" }, { "subclaim_id": "SC5", "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": "Organoid aging-like methylation provides a plausible functional precursor and rare constitutional epimutations establish epigenetic predisposition. No examined positive native epithelial lineage study isolates spontaneously arising methylation as independently initiating and sustaining a cancer field. Engineered p16 tumor sufficiency is narrower than natural clonal-field independence.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Spontaneous promoter hypermethylation in morphologically normal epithelium independently initiates and sustains pre-neoplastic clonal field expansion and subsequent carcinogenesis.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Native in-vivo incidence and inflammatory interventions cross thresholds for defined SC2/SC3 scopes. They cannot lift SC5 without a positive test of spontaneous independent native clonal initiation. The Γ simplified-system cap binds the organoid-to-native-field transfer, and the Β association cap binds causal transfer from prospective marker prediction.", "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": [ "Spatial normal-tissue methylation and later disease association do not identify an independently expanding causal clone.", "Organoid transformation, engineered cis-sequence methylation and constitutional epimutations require separate scope labels; no absence-of-detected-mutation claim is whole-genome proof." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Normal epithelial methylation fields are reproducible, spatially measurable and often associated with neoplasia. This is robust existence/association evidence, with locus and organ-specific nulls; the Β cancer-association cap does not deny their existence.", "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": "PMID25866970, PMID25061879, PMID37143122", "gamma_hard_rules_triggered": [ "Spatial normal-tissue methylation and later disease association do not identify an independently expanding causal clone.", "Organoid transformation, engineered cis-sequence methylation and constitutional epimutations require separate scope labels; no absence-of-detected-mutation claim is whole-genome proof." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Endogenous-locus engineered p16 methylation raises spontaneous tumor incidence without a required engineered oncogene. Inserted-sequence controls and reactivation distinguish silencing from simple insertion effects. Small mixed-background cohorts and lack of adult native field demethylation/incidence rescue keep this at context-specific Ε.", "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": "PMID27992956, PMID19821005, PMID20124475, PMID20980348", "gamma_hard_rules_triggered": [ "Spatial normal-tissue methylation and later disease association do not identify an independently expanding causal clone.", "Organoid transformation, engineered cis-sequence methylation and constitutional epimutations require separate scope labels; no absence-of-detected-mutation claim is whole-genome proof." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Inflammation suppression despite retained colonization, exposure-duration contrasts, withdrawal and human longitudinal biopsies establish defined inflammatory routes to methylation. Persistence is partly marker-specific; broad immunosuppression, repair changes and limited original-body access prevent a universally resolved induction mechanism.", "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": [ "Spatial normal-tissue methylation and later disease association do not identify an independently expanding causal clone.", "Organoid transformation, engineered cis-sequence methylation and constitutional epimutations require separate scope labels; no absence-of-detected-mutation claim is whole-genome proof." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Several prospective cohorts demonstrate later cancer or neoplasia associations, including independent primary-incidence and metachronous cohorts. The Β association cap applies to causal interpretation, not to the validated predictive signal. Marker alteration has not itself been selectively shown to change human incidence.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC5", "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": [ "Spatial normal-tissue methylation and later disease association do not identify an independently expanding causal clone.", "Organoid transformation, engineered cis-sequence methylation and constitutional epimutations require separate scope labels; no absence-of-detected-mutation claim is whole-genome proof." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Organoid aging-like methylation provides a plausible functional precursor and rare constitutional epimutations establish epigenetic predisposition. No examined positive native epithelial lineage study isolates spontaneously arising methylation as independently initiating and sustaining a cancer field. Engineered p16 tumor sufficiency is narrower than natural clonal-field independence.", "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": "Joint normal-cell genotype, methylome and lineage follow-up with causal fitness perturbation rather than association alone." }, { "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": [ "[38] Locus-directed suppression increases replication and p16 restoration reverses the phenotype.", "[39] Engineered promoter methylation represses p16 and raises spontaneous tumor incidence without a required engineered oncogene; inserted-sequence controls and expression restoration support mechanism.", "[49] p16 epimutation cooperates with Apc, changes immune milieu and tumor progression; targeted demethylation restores p16 in fibroblasts." ], "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": [ "[38] Locus-directed suppression increases replication and p16 restoration reverses the phenotype.", "[39] Engineered promoter methylation represses p16 and raises spontaneous tumor incidence without a required engineered oncogene; inserted-sequence controls and expression restoration support mechanism.", "[49] p16 epimutation cooperates with Apc, changes immune milieu and tumor progression; targeted demethylation restores p16 in fibroblasts." ], "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": [ "[38] Locus-directed suppression increases replication and p16 restoration reverses the phenotype.", "[39] Engineered promoter methylation represses p16 and raises spontaneous tumor incidence without a required engineered oncogene; inserted-sequence controls and expression restoration support mechanism.", "[49] p16 epimutation cooperates with Apc, changes immune milieu and tumor progression; targeted demethylation restores p16 in fibroblasts." ], "what_would_cross_it": "Adult native epithelial methylation induction with sequence-preserving catalytic controls and locus-specific reversal of spontaneous tumor incidence in independently replicated tissues." }, { "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": [ "[4] Methylation burden increases with exposure and partly persists after withdrawal.", "[16] Successful eradication reduces marker methylation with marker-specific kinetics but leaves residual levels above uninfected controls.", "[60] Suppressing inflammation leaves bacterial colonization intact but blocks methylation induction; withdrawal leaves a residual component.", "[62] Strong proliferation alone fails to induce the same methylation; inflammatory type matters." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[4] Methylation burden increases with exposure and partly persists after withdrawal.", "[16] Successful eradication reduces marker methylation with marker-specific kinetics but leaves residual levels above uninfected controls.", "[60] Suppressing inflammation leaves bacterial colonization intact but blocks methylation induction; withdrawal leaves a residual component.", "[62] Strong proliferation alone fails to induce the same methylation; inflammatory type matters." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "no", "supporting_evidence": [ "[4] Methylation burden increases with exposure and partly persists after withdrawal.", "[16] Successful eradication reduces marker methylation with marker-specific kinetics but leaves residual levels above uninfected controls.", "[60] Suppressing inflammation leaves bacterial colonization intact but blocks methylation induction; withdrawal leaves a residual component.", "[62] Strong proliferation alone fails to induce the same methylation; inflammatory type matters." ], "what_would_cross_it": "Cell-resolved inflammatory withdrawal with selective epithelial mediator perturbation and matched restoration, preserving proliferation, immune composition and viability." }, { "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": "A calibrated externally validated incidence model can strengthen prediction; a causal claim additionally needs selective marker/pathway alteration that changes incidence with confounding controlled." }, { "subclaim_id": "SC5", "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": "Prospective native lineage tracing of spontaneous epimutant normal epithelial clones with whole-genome profiling and selective methylation reversal that removes their fitness/cancer advantage before acquired drivers." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Yu inserted control sequence, retained neighboring promoters and methylation-linked expression restoration distinguish targeting from generic insertion.", "Niwa suppresses inflammation while colonization remains, and Hur separates proliferation from methylation-inducing inflammatory types.", "Asada prespecifies markers and excludes first-year occult events; Yamada measures incident primary cancer in a different cohort.", "Left-colon and LINE-1 nulls preserve organ/marker boundaries; targeted mutation absence is not absence of all genetic variants." ], "note": "Organ, anatomical segment, prior cancer, acquired versus constitutional methylation, inflammatory exposure and genotype define boundaries before results. Positive right-colon and gastric signals coexist with left-colon, prostate-locus and LINE-1 nulls. Case-selected post-eradication persistence cannot define a responder-only causal population." }, "falsification_patterns_met": [ { "pattern": "Predicted generality fails in a prespecified tissue", "evidence": "PMID28540987 finds most tested fields absent in left-colon adjacent mucosa; PMID25859284 finds no LINE-1 field. Marker-panel nulls restrict scope rather than erase all methylation fields.", "downgrade_applied": false }, { "pattern": "Proposed autonomous feature requires cooperating context in a functional test", "evidence": "PMID30753828 culture-associated methylation accelerates Braf-dependent transformation; PMID37143122 tests Apc cooperation. Yu supports narrower engineered susceptibility.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Prediction substituted for causality", "where": "Prospective HRs show temporal risk association, not that the methylated marker independently creates cancer." }, { "pitfall": "Engineering substituted for spontaneous initiation", "where": "Yu uses an altered cis DNA sequence; spontaneous subsequent tumors do not make the initiating epimutation naturally acquired." }, { "pitfall": "Genetic-only rival overclaimed", "where": "Constitutional MLH1 and targeted p16 support epigenetic predisposition; normal driver clones can remain functional and nonmalignant." }, { "pitfall": "Provider retrieval absence treated as missing literature", "where": "Consensus missed prospective cohorts and attached Niwa primary results to a narrative review identifier; corrected canonical records govern." } ], "causal_tally_audit": { "tally_claimed_by_document": 26, "tally_after_audit": 26, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Shared cohorts, experimental platforms, transgenic lineages and repeated outcomes do not constitute fully independent causal lines." ] }, "steelman": { "case_one_rung_higher": "Δ steelman: Yu is a native locus and raises spontaneous tumor incidence, while constitutional MLH1 cases have no detected cis mutation. Those results establish defined epigenetic susceptibility, but neither demonstrates naturally acquired epithelial field initiation and sustained clonal growth independently of additional changes. The preregistered SC5 positive crossing is missing.", "case_one_rung_lower": "Β steelman: normal fields are largely biomarkers. Tao gene-function and culture-aging contrasts, locus-specific p16 controls and epimutation predisposition provide real mechanistic plausibility beyond spatial association, retaining Γ for the nominal gate.", "which_rejected": "Γ retains causal epigenetic contributions while refusing scope transfer to autonomous naturally acquired epithelial field initiation.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: In a defined uninjured adult epithelial lineage, follow naturally arising promoter epimutant clones with joint genome/methylome profiling, then selectively reverse the candidate methylation while preserving DNA sequence and compare clone fitness and incident cancer with catalytic-dead and matched-expression rescue controls." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "63 primary reports examined. Moderate rests on evidence density and reproducibility, not on reading access: the two engineered p16 reports share a single allele and are not independent causal lines, the organoid result is culture- and transplantation-dependent, the field evidence is largely cross-sectional, the prospective cohorts carry wide intervals, and organ and segment nulls plus one abstract-versus-body discrepancy remain unresolved. Confidence bounds the evidence base, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The registered scope-matched gate SC5 gives Γ. SC2 and SC3 reach Ε in defined engineered or inflammatory settings, while SC1 and SC4 remain Β for causal inference from association. Weakest-link sensitivity is Β. Predictive value and causal contributions are retained without substituting for spontaneous independent field initiation." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Cancer is not established as the sole producer of the field (step1), and functional methylation interventions establish causal contributions (step2). Naturally independent rate-limiting initiation is not established (step3), nor is universal methylation necessity (step4). Defined methylation loss of suppressor function amplifies susceptibility and maintains progression with cooperating context, matching step5. This does not make every methylated marker functional.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Recent Yang mechanistic and Yamada prospective reports test cooperation and risk; no verified ongoing native spontaneous-field independence experiment is claimed.", "justification": "Recent Yang mechanistic and Yamada prospective reports test cooperation and risk; no verified ongoing native spontaneous-field independence experiment is claimed." }, "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": "In a defined uninjured adult epithelial lineage, follow naturally arising promoter epimutant clones with joint genome/methylome profiling, then selectively reverse the candidate methylation while preserving DNA sequence and compare clone fitness and incident cancer with catalytic-dead and matched-expression rescue controls.", "readout": "Native clone survival/expansion, suppressor expression, new driver acquisition and spontaneous cancer incidence", "critical_control": "Age/organ/exposure matching, cell-state and inflammation controls, off-target methylome/genome audit, selective reversal and matched restoration", "supporting_result": "Methylation precedes and independently confers clonal expansion and cancer propensity; selective reversal removes the advantage and matched restoration returns it without cooperating genomic changes", "falsifying_result": "Clone fitness follows driver mutations or inflammatory state, selective reversal leaves progression intact, or only engineered/cooperating contexts produce cancer" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Joint longitudinal genome/epigenome lineage data are needed to identify whether spontaneous methylation precedes and causes native clonal fitness.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Separate marker burden from the specific functional methylated drivers that mediate incidence.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Test locus-specific adult epithelial reversal rather than relying on global demethylating drug effects.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Externally validate prospective gastric thresholds and colorectal OMP/SWEPIC incidence prediction without conflating case-control AUC with future risk.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Resolve organ and segment boundaries with matched cell composition, age and exposure controls.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Distinguish constitutional epimutations from acquired normal epithelial fields and quantify undetected genetic contributions.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Examine the linked MSH2 erratum body and complete supplements before publication-grade mechanism claims.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Reconcile the single-locus abstract/body discrepancy in the left-colon null report before quoting that estimate.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-09", "reviewer": "Codex", "evidence_base_note": "63 primary reports; literature cutoff 2026-10-09; 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": "Upper rungs are live without a clinical RCT: native lineage and locus-specific interventions, natural constitutional epimutations, withdrawal and independent incidence cohorts can exclude different errors. Together they support a cooperative causal model, while the nominal independent field still lacks sequence-preserving native initiation/rescue." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Upper rungs are live without a clinical RCT: native lineage and locus-specific interventions, natural constitutional epimutations, withdrawal and independent incidence cohorts can exclude different errors. Together they support a cooperative causal model, while the nominal independent field still lacks sequence-preserving native initiation/rescue." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Upper rungs are live without a clinical RCT: native lineage and locus-specific interventions, natural constitutional epimutations, withdrawal and independent incidence cohorts can exclude different errors. Together they support a cooperative causal model, while the nominal independent field still lacks sequence-preserving native initiation/rescue." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Upper rungs are live without a clinical RCT: native lineage and locus-specific interventions, natural constitutional epimutations, withdrawal and independent incidence cohorts can exclude different errors. Together they support a cooperative causal model, while the nominal independent field still lacks sequence-preserving native initiation/rescue." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Upper rungs are live without a clinical RCT: native lineage and locus-specific interventions, natural constitutional epimutations, withdrawal and independent incidence cohorts can exclude different errors. Together they support a cooperative causal model, while the nominal independent field still lacks sequence-preserving native initiation/rescue." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 63, "claims_total": 69, "claims_verified": 69, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 63, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "DDR, mutation burden and repair-promoter methylation distinguish metaplastic states. Cross-sectional DDR markers and methylation do not establish an independent initiating clone.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C2", "text": "SMARCA1/ACTL6B methylation occurs in noncancerous tissue; remodeler depletion promotes cancer-cell growth. Mutation and methylation coexist; cancer-cell depletion does not reproduce spontaneous epithelial initiation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C3", "text": "IM has a distinctive methylome and NOS2 induction accelerates methylation. An IM signature and artificial NOS2 induction do not show methylation alone initiates cancer.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C4", "text": "Methylation burden increases with exposure and partly persists after withdrawal. Persistence is not proof of autonomous cancer initiation; related gastric platform is grouped.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C5", "text": "LINE-1 hypomethylation associates with multiple cancers and predicts metachronous neoplasms. This is hypomethylation, not the proposed promoter hypermethylation; observational prediction is not causation.", "carries_number": true, "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": "GPX3 promoter methylation rises through metaplasia, dysplasia and adenocarcinoma with reduced expression. Stage association cannot resolve temporal initiation or independent clonal growth.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C7", "text": "Genetic and epigenetic profiles identify distinct mutation-defined colitis cancer groups. Tumor profiling is not a prospective test of normal methylated clone initiation.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C8", "text": "A stable early-onset case inherited a constitutional epimutation from a mosaic asymptomatic mother without detected sequence alteration. Rare constitutional predisposition differs from acquired epithelial field expansion; genomic absence remains bounded by detection.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "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": "DNMT inhibition reduces tumorigenesis and persistent inflammatory methylation; derived tumoroids differ in proliferation. Broad drug effects, inflammatory context and shared precursor model prevent isolated spontaneous methylation sufficiency.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C10", "text": "Demethylating treatment reduces cancer incidence with lower epithelial methylation. Inflammatory cytokines also change and carcinogen exposure remains; no locus-specific mediation rescue or spontaneous field test.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C11", "text": "Preselected mucosal miR-124a-3 methylation predicts authentic later cancers with adjusted HR 2.30 and explicit early-event exclusion. Three-year follow-up, modest events and residual confounding limit causality; not all marker or endpoint analyses are significant.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Patients and methods, 2:Results. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C12", "text": "Normal antral tissue in nodular gastritis has higher tumor-suppressor methylation, including in patients without cancer. Small cross-sectional groups and tissue-state effects do not isolate inflammatory causation or initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C13", "text": "MSH2 loss prevents early inflammation-associated epigenetic alterations and later hypermethylation. MSH2 also affects repair and tumor biology; linked erratum body remains unexamined, limiting fine mechanistic certainty.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C14", "text": "Gastritis activity correlates with promoter gains and repeat losses of methylation. Serological covariation is not an intervention or independent epimutation initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C15", "text": "Antibiotics reduce inflammation, methylation markers and colon tumor burden together. Multiple pathways change; methylation mediation is not isolated and the model is not spontaneous.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C16", "text": "Successful eradication reduces marker methylation with marker-specific kinetics but leaves residual levels above uninfected controls. Nonrandom intervention and cell-composition changes limit mediation; residual risk does not establish autonomous methylated clones.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C17", "text": "Probable drivers occur in about 1% of middle-age crypts; normal clonal evolution is genetically measurable. Driver presence is not sufficient for cancer and epigenomes were not jointly measured; mutation-first is not universally proved.", "carries_number": true, "load_bearing_for": [ "SC5" ], "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": "IBD increases mutations and millimetre-scale clonal expansion with tissue-specific positive selection. Control crypts reuse prior normal-colon publication; genetic selection does not exclude cooperative epigenetic effects.", "carries_number": false, "load_bearing_for": [ "SC5" ], "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": "Normal epithelium becomes colonized by positively selected mutant clones, with NOTCH1 more prevalent than in cancers. Cross-sectional clonal genetics does not show every clone is malignant or resolve methylation's additional contribution.", "carries_number": true, "load_bearing_for": [ "SC5" ], "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": "Smoking increases mutational burden and driver prevalence; cessation associates with less-mutated cells. Colony culture and cross-sectional sampling constrain selection inference; no joint methylome lineage test.", "carries_number": false, "load_bearing_for": [ "SC5" ], "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": "Distinct drivers and trisomies occur in normal glands; clone prevalence depends on age and inflammation, with normal/cancer CTNNB1 spectra differing. Normal clones are not equivalent to cancer and methylation is not jointly perturbed; cancer-bearing donors contribute samples.", "carries_number": true, "load_bearing_for": [ "SC5" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:Driver mutations in gastric glands. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C22", "text": "Positive selection produces abundant cancer-gene mutant clones while tissue remains functional. Four donors and targeted genes constrain coverage; genetic clone existence does not exclude epigenetic cooperation.", "carries_number": false, "load_bearing_for": [ "SC5" ], "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": "Outlier-sensitive statistical approaches detect reproducible premalignant methylation field patterns. Reused cohorts and algorithm comparisons are not independent causal interventions; biological selection is inferred.", "carries_number": false, "load_bearing_for": [ "SC1" ], "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": "A widespread histologically normal prostate field profile validates beyond immediate tumor proximity. Most altered loci are hypomethylated; cross-sectional tissue cannot establish initiation direction.", "carries_number": false, "load_bearing_for": [ "SC1" ], "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": "Age- and disease-associated CGI patterns discriminate normal mucosal groups. Classifier accuracy within sampled groups does not demonstrate prospective risk or independent initiation.", "carries_number": false, "load_bearing_for": [ "SC1" ], "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": "Field methylation is gene- and case-specific; GSTP1 field change is absent while some loci extend beyond tumor. Small spatial sampling and occult-cell effects remain; lack of one marker is not absence of all fields.", "carries_number": true, "load_bearing_for": [ "SC1" ], "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": "Histologically negative margins often share tumor methylation but no significant recurrence correlation is found. Twenty patients and few recurrences limit power; negative margins do not prove independent normal clones.", "carries_number": false, "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": "MGMT/ADAMTS14 normal-mucosal fields correlate with age, but MGMT methylation has no significant KRAS/TP53 or exome G-to-A association. Null mutation association does not rule out other methylation consequences; cross-sectional ancestry associations are not causal mechanisms.", "carries_number": true, "load_bearing_for": [ "SC1", "SC5" ], "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": "FAT4 methylation silences expression and is associated with infection and cancer in noncancerous mucosa. Broad demethylation restores expression without demonstrating native field initiation or incidence.", "carries_number": true, "load_bearing_for": [ "SC1" ], "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": "EYA4 methylation is elevated beyond the tumor in UC cases with synchronous CRC. Synchronous case-control signal, wide odds-ratio uncertainty and incomplete tissue availability limit prospective inference.", "carries_number": true, "load_bearing_for": [ "SC1" ], "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": "MGMT-deficient mucosal patches associate more often with MSI cancers. The proposed ordering from MGMT loss to MMR deficiency is inferred, not traced prospectively or selectively rescued.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "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": "Ipsilateral normal breast shows CGI-shore changes relative to contralateral epithelium. Nine cancer-bearing women; contralateral tissue is not a cancer-free population and spatial ordering is not temporal causality.", "carries_number": false, "load_bearing_for": [ "SC1" ], "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": "LINE-1 field hypomethylation is absent; segment-specific methylation differences are detected. This negative result addresses repeat methylation, not every promoter field; rectal ACF differ from right-colon adenomas.", "carries_number": true, "load_bearing_for": [ "SC1" ], "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": "miR-34b/c methylation tracks multiple gastric cancer and restoration suppresses cancer-cell growth. Synthetic RNA restoration in cancer cells does not isolate spontaneous field initiation in vivo.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "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": "New correlated mucosal methylation markers discriminate gastric cancer from atrophic controls. Case-control discrimination is not prospective incidence; shared exposure and marker covariance remain.", "carries_number": false, "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": "Relative predictive contribution of genetic and epigenetic alterations differs by tissue. Risk groups are defined partly by existing cancer; targeted mutation assays do not establish epigenetic independence.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "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": "p16 silencing associates with CTCF boundary loss and altered protein regulation. Established cancer cells and correlated chromatin changes do not identify spontaneous normal epithelial field initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "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": "Locus-directed suppression increases replication and p16 restoration reverses the phenotype. Fibroblast replication is not epithelial malignancy or spontaneous in-vivo incidence; engineered delivery defines scope.", "carries_number": true, "load_bearing_for": [ "SC2" ], "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": "Engineered promoter methylation represses p16 and raises spontaneous tumor incidence without a required engineered oncogene; inserted-sequence controls and expression restoration support mechanism. The initiating allele is engineered DNA; mixed backgrounds, small tumor cohorts, non-epithelial tumor spectrum and absent whole-genome lineage/rescue constrain natural-field transfer.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 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": "C40", "text": "KRAS-linked ZNF304 recruitment mediates DNMT1-associated CIMP silencing. Cancer-cell dependency is not universal mutation-first initiation; related RNAi platform is grouped.", "carries_number": true, "load_bearing_for": [ "SC5" ], "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": "BRAF-MAFG corepressor pathway directs methylation-linked silencing in two cancer settings. Shares pathway/platform with earlier CRC report; no proof that all natural methylation fields originate genetically.", "carries_number": false, "load_bearing_for": [ "SC5" ], "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": "Spontaneous culture-associated methylation creates Wnt/stemness changes and sharply accelerates Braf-dependent transformation. Culture aging is not chronological native epithelium; Braf is required in the tested transformation comparison and some selected outgrowths acquire Wnt mutations.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph8, 1:RESULTS:paragraph11, 1:RESULTS:paragraph12, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph15, 1:RESULTS:paragraph16, 1:RESULTS:paragraph17. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C43", "text": "MAFG depletion resolves an oncogene-directed MLH1/CIMP repression pathway. Related study line and established tumor cells limit initiation transfer; does not erase epigenetic-first sensitization.", "carries_number": true, "load_bearing_for": [ "SC5" ], "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": "Soma-wide allele-specific MLH1 methylation accompanies multiple mismatch-repair-deficient tumors without detected MMR mutation. Rare constitutional predisposition and bounded mutation detection do not establish common acquired epithelial field expansion.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "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": "Ten carriers lack detected cis nucleotide/structural variants; the focal methylation event can erase across generations. Other CNVs in two cases and unsolved mechanism constrain pure epigenetic independence; rare constitutional scope remains.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "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": "MLH1 promoter genotype alters AP4 binding and shore methylation. Local genetic regulation need not explain all MLH1 epimutations or spontaneous field clones.", "carries_number": true, "load_bearing_for": [ "SC5" ], "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": "Outlier fields enrich architecture-factor loci and progress in paired cancer samples. Computational cellular-mixture adjustment and cross-sectional tissue cannot establish clonal causality; related outlier algorithms share assumptions.", "carries_number": false, "load_bearing_for": [ "SC1" ], "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": "Single-marker methylation correlates with genome-wide burden and candidate driver methylation. Biomarker covariance is not mediation or independent initiation; discovery and validation sample roles differ.", "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": "p16 epimutation cooperates with Apc, changes immune milieu and tumor progression; targeted demethylation restores p16 in fibroblasts. Shared cis-element lineage with Yu; tumors arise in Apc-mutant context and broad drug/immune effects prevent autonomous initiation inference.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph0, 2:Results:paragraph2, 2:Results:paragraph3, 2:Results:paragraph5, 2:Results:paragraph17. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C50", "text": "Methylation is strongly associated with infection and, after exposure stratification, with existing cancer. Cross-sectional exposure signal and variability are not independent epigenetic initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C51", "text": "Post-infection marker methylation increases across cancer-risk groups after atrophy adjustment. Existing multiple cancers define risk groups; association does not trace or perturb a field clone.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C52", "text": "Marker methylation improves after eradication in some groups but persists with metachronous cancer. Outcome-selected groups and limited sample sizes are not a preregistered independent causal test.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C53", "text": "Baseline miR-34b/c predicts later cancer after covariate adjustment in 129 patients. Seventeen events and observational tissue markers do not establish independent methylation-driven initiation.", "carries_number": true, "load_bearing_for": [ "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": "Baseline MOS predicts later metachronous neoplasms with adjusted HR 4.76. Only 124 of 294 completed the protocol; outcome mixes adenomas and seven cancers and threshold requires external validation.", "carries_number": true, "load_bearing_for": [ "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": "Early polycomb-target methylation and local expression changes persist through progression. Stage ordering is not prospective clonal tracing; HPV context precludes autonomous epigenetic initiation inference.", "carries_number": false, "load_bearing_for": [ "SC1" ], "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": "Outlier methylation phenotype occurs in 15/77 CRC cases versus 0/68 controls with transcriptional changes. Case-control OMP signal is not prospective incidence or proof of microbial or methylation causal ordering.", "carries_number": true, "load_bearing_for": [ "SC1" ], "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": "558 loci distinguish adenoma-adjacent mucosa, with external validation and age/cell-composition checks. AUC is cross-sectional classification, not prediction of subsequent incident cancer; many loci associate with age.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph4, 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph10, 1:Results:paragraph14, 1:Results:paragraph15. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C58", "text": "Crypt methylation varies within donors and associates with age/disease, with all-or-none CGI patterns. Clonal units are sampled cross-sectionally without genome/epigenome fate tracking; combined mutation mechanism is proposed.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C59", "text": "Most candidate methylation fields are absent despite strong tumor signals; adjacent hotspots are negative. Candidate panel and modest cohort cannot exclude every epimutation; abstract/body single-locus estimates differ and are not pooled.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:RESULTS. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C60", "text": "Suppressing inflammation leaves bacterial colonization intact but blocks methylation induction; withdrawal leaves a residual component. Broad immunosuppression and exposure-defined tissue do not isolate autonomous methylation-mediated cancer initiation.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C61", "text": "Multiple assays detect MGMT fields well beyond tumors and associate tumor methylation with KRAS transitions. Normal-mucosal mutation association is nonsignificant; ordering and clonal fitness are not directly tested.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C62", "text": "Strong proliferation alone fails to induce the same methylation; inflammatory type matters. Related gastric platform and different exposures limit independent replication; outcome is methylation rather than cancer incidence.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C63", "text": "1624 followed participants with 27 incident cancers validate RIMS1 risk gradients with adjusted HR 5.7. Wide interval and atrophy-selected population constrain transfer; marker burden validation uses separate archived samples, and methylation is not experimentally altered.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC1", "text": "Normal epithelial methylation fields are reproducible, spatially measurable and often associated with neoplasia. This is robust existence/association evidence, with locus and organ-specific nulls; the Β cancer-association cap does not deny their existence.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 5, 6, 12, 14, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 47, 48, 50, 51, 55, 56, 57, 58, 59, 61 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC2", "text": "Endogenous-locus engineered p16 methylation raises spontaneous tumor incidence without a required engineered oncogene. Inserted-sequence controls and reactivation distinguish silencing from simple insertion effects. Small mixed-background cohorts and lack of adult native field demethylation/incidence rescue keep this at context-specific Ε.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 8, 9, 10, 34, 37, 38, 39, 42, 44, 45, 49 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC3", "text": "Inflammation suppression despite retained colonization, exposure-duration contrasts, withdrawal and human longitudinal biopsies establish defined inflammatory routes to methylation. Persistence is partly marker-specific; broad immunosuppression, repair changes and limited original-body access prevent a universally resolved induction mechanism.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 3, 4, 9, 10, 12, 13, 14, 15, 16, 50, 52, 60, 62 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC4", "text": "Several prospective cohorts demonstrate later cancer or neoplasia associations, including independent primary-incidence and metachronous cohorts. The Β association cap applies to causal interpretation, not to the validated predictive signal. Marker alteration has not itself been selectively shown to change human incidence.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 5, 11, 27, 35, 48, 51, 52, 53, 54, 57, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC5", "text": "Organoid aging-like methylation provides a plausible functional precursor and rare constitutional epimutations establish epigenetic predisposition. No examined positive native epithelial lineage study isolates spontaneously arising methylation as independently initiating and sustaining a cancer field. Engineered p16 tumor sufficiency is narrower than natural clonal-field independence.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 1, 2, 7, 8, 17, 18, 19, 20, 21, 22, 28, 31, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 49, 58, 59, 61 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CH", "text": "Methylation fields predict risk and can contribute causally, but spontaneous independent initiation of cancer fields remains unestablished.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 39, 11, 42, 49, 63, 59 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-09", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Krishnan V, Lim DXE, Hoang PM et al. DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia. Gut. 2020.", "tier": "A", "kind": "primary", "pmid": "31937549", "doi": "10.1136/gutjnl-2019-319002", "url": "https://pubmed.ncbi.nlm.nih.gov/31937549/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31937549", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC5" ] }, { "n": 2, "citation": "Takeshima H, Niwa T, Takahashi T et al. Frequent involvement of chromatin remodeler alterations in gastric field cancerization. Cancer letters. 2015.", "tier": "A", "kind": "primary", "pmid": "25462860", "doi": "10.1016/j.canlet.2014.11.038", "url": "https://pubmed.ncbi.nlm.nih.gov/25462860/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25462860", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC5" ] }, { "n": 3, "citation": "Takeuchi C, Yamashita S, Liu YY et al. Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation. Gut. 2024.", "tier": "A", "kind": "primary", "pmid": "37751933", "doi": "10.1136/gutjnl-2023-329492", "url": "https://pubmed.ncbi.nlm.nih.gov/37751933/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37751933", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC3" ] }, { "n": 4, "citation": "Takeshima H, Niwa T, Toyoda T et al. Degree of methylation burden is determined by the exposure period to carcinogenic factors. Cancer science. 2017.", "tier": "A", "kind": "primary", "pmid": "27992956", "doi": "10.1111/cas.13136", "url": "https://pubmed.ncbi.nlm.nih.gov/27992956/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "Ushijima-gerbil-inflammation-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC3" ] }, { "n": 5, "citation": "Kamiyama H, Suzuki K, Maeda T et al. DNA demethylation in normal colon tissue predicts predisposition to multiple cancers. 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Carcinogenesis. 2010.", "tier": "A", "kind": "primary", "pmid": "20924086", "doi": "10.1093/carcin/bgq203", "url": "https://pubmed.ncbi.nlm.nih.gov/20924086/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20924086", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C34", "CSC1", "CSC2" ] }, { "n": 35, "citation": "Maeda M, Yamashita S, Shimazu T et al. Novel epigenetic markers for gastric cancer risk stratification in individuals after Helicobacter pylori eradication. 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Proceedings of the National Academy of Sciences of the United States of America. 2018.", "tier": "A", "kind": "primary", "pmid": "29358395", "doi": "10.1073/pnas.1717340115", "url": "https://pubmed.ncbi.nlm.nih.gov/29358395/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29358395", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C36", "CSC1", "CSC5" ] }, { "n": 37, "citation": "Witcher M, Emerson BM. Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary. 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