High DNA methylation age deceleration defines an aggressive phenotype with immunoexclusion environments in endometrial carcinoma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:37388735", "kind": "science-record", "revision": 3, "content_hash": "sha256:57885229599809ef575c3dae46eae29177e2f6c3a3d576fab09e0a2a70b9a24a", "created_at": "2026-11-01T19:02:09Z", "updated_at": "2026-11-01T22:52:14Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "High DNA methylation age deceleration defines an aggressive phenotype with immunoexclusion environments in endometrial carcinoma.", "doi": "10.3389/fimmu.2023.1208223", "pmid": "37388735", "authors": ["Jing Hao", "Tiantian Liu", "Yuchen Xiu", "Huiyang Yuan", "Dawei Xu"], "journal": "Frontiers in immunology", "year": 2023, "abstract": "Like telomere shortening, global DNA hypomethylation occurs progressively with cellular divisions or in vivo aging and functions as a mitotic clock to restrain malignant transformation/progression. Several DNA-methylation (DNAm) age clocks have been established to precisely predict chronological age using normal tissues, but show DNAm age drift in tumors, which suggests disruption of this mitotic clock during carcinogenesis. Little is known about DNAm age alterations and biological/clinical implications in endometrial cancer (EC). Here we address these issues by analyzing TCGA and GSE67116 cohorts of ECs. Horvath clock analysis of these tumors unexpectedly revealed that almost 90% of them exhibited DNAm age deceleration (DNAmad) compared to patient chronological age. Combined with an additional clock named Phenoage, we identified a subset of tumors (82/429) with high DNAmad (hDNAmad+) as assessed by both clocks. Clinically, hDNAmad+ tumors were associated with advanced diseases and shorter patient survival, compared to hDNAmad- ones. Genetically, hDNAmad+ tumors were characterized by higher copy number alterations (CNAs) whereas lower tumor mutation burden. Functionally, hDNAmad+ tumors were enriched with cell cycle and DNA mismatch repair pathways. Increased PIK3CA alterations and downregulation of SCGB2A1, the inhibitor of PI3K kinase, in hDNAmad+ tumors, might promote tumor growth/proliferation and stemness. In addition, the inactivation of aging drivers/tumor suppressors (TP53, RB1, and CDKN2A) while enhanced telomere maintenance occurred more frequently in hDNAmad+ tumors, which supports sustained tumor growth. Prominently, hDNAmad+ tumors were featured with immunoexclusion microenvironments, accompanied by significantly higher levels of VTCN1 expression while lower PD-L1 and CTLA4 expression, which indicates their poor response to immune checkpoint inhibitor (ICI)-based immunotherapy. We further showed significantly higher levels of DNMT3A and 3B expression in hDNAmad+ than in hDNAmad- tumors. Thus, the tumor suppressive function of aging-like DNA hypomethylation is severely impaired in hDNAmad+ tumors, likely due to enhanced expression of DNMT3A/3B and dysregulated aging regulators. Our findings not only enrich biological knowledge of EC pathogenesis but also help improve EC risk stratification and precision ICI immunotherapy.", "claims": [{"id": "claim-method", "statement": "According to data distributions, Student’s t-test, Wilcox and K-W sum tests, and Chi2- or Fish exact tests were used for analysis. The correlation between DNAm age and chronological age was evaluated by Pearson coefficient correlation. Kaplan–Meier analysis with log-rank test was carried out to evaluate overall- and progression-free survivals (OS and PFS) among groups. The effect of various quantitative variables on OS and PFS was measured by univariate and multivariate Cox regression analyses. P < 0.05 were considered statistically significant.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:37388735", "locator": "sections[11] \"Statistical analyses\" paragraph 2", "quote": "According to data distributions, Student’s t-test, Wilcox and K-W sum tests, and Chi2- or Fish exact tests were used for analysis. The correlation between DNAm age and chronological age was evaluated by Pearson coefficient correlation. Kaplan–Meier analysis with log-rank test was carried out to evaluate overall- and progression-free survivals (OS and PFS) among groups. The effect of various quantitative variables on OS and PFS was measured by univariate and multivariate Cox regression analyses. P < 0.05 were considered statistically significant."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:37388735", "locator": "sections[21] \"Data availability statement\" paragraph 2", "quote": "The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors."}], "state": "complete"}, {"id": "claim-target-result", "statement": "High DNAmad identified by both the Horvath and Phenoage clocks was associated with aggressive endometrial cancer, shorter survival, genomic alterations, and an immunoexclusion microenvironment.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:37388735", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Combined with an additional clock named Phenoage, we identified a subset of tumors (82/429) with high DNAmad (hDNAmad+) as assessed by both clocks."}, {"asset": "source:pmid:37388735", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Clinically, hDNAmad+ tumors were associated with advanced diseases and shorter patient survival, compared to hDNAmad- ones."}, {"asset": "source:pmid:37388735", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Prominently, hDNAmad+ tumors were featured with immunoexclusion microenvironments, accompanied by significantly higher levels of VTCN1 expression while lower PD-L1 and CTLA4 expression, which indicates their poor response to immune checkpoint inhibitor (ICI)-based immunotherapy."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "High DNAmad identified by both the Horvath and Phenoage clocks was associated with aggressive endometrial cancer, shorter survival, genomic alterations, and an immunoexclusion microenvironment.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:37388735"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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The GSE67116 c", "number data were downloaded from Feb. 2022. RNA sequencing results of those tumors were also downloaded"], "order_basis": "paper_text_order:2864", "id": "assay:3"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["cox_ph"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["According to data distributions, Student’s t-test, Wilcox and K-W sum tests, and Chi2- or Fish exact tests were used for analysis. The correlation between DNAm age and chronological age was evaluated by Pearson coefficient correlation. Kaplan–Meier analysis with log-rank test was carried out to evaluate overall- and progression-free survivals (OS and PFS) among groups. The effect of various quantitative variables on OS and PFS was measured by univariate and multivariate Cox regression analyses. P < 0.05 were considered statistically significant."], "order_basis": "consumes_earlier_output", "id": "assay:4"}]}