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Here, we characterize the tumor multi-omic landscape of endometrial cancers that have developed on a background of lifelong germline genetic liability to elevated BMI. Methods: We built a polygenic score (PGS) for BMI in women using data on independent, genome-wide significant variants associated with adult BMI in 434,794 women. We performed germline (blood) genotype quality control and imputation on data from 354 endometrial cancer cases from The Cancer Genome Atlas (TCGA). We assigned each case in this TCGA cohort their genetically predicted BMI based on the BMI PGS. Multivariable generalized linear models adjusted for age, stage, microsatellite status and genetic principal components were used to test for associations between the BMI germline PGS and endometrial cancer tumor genome-wide genomic, transcriptomic, proteomic, epigenomic and immune traits in TCGA. Results: High BMI germline PGS was associated with (i) upregulated tumor gene expression in IL6-JAK-STAT3 signaling (FDR = 4.2 \u00d7 10\u22127) and in other immune\/inflammatory pathways; (ii) increased estimated intra-tumor activated mast cell infiltration (FDR = 0.008); and (iii) increased single base substitution (SBS) mutational signature 1 (FDR = 0.03), implicating age-related mutagenesis. In contrast, BMI at diagnosis associated with elevated progesterone receptor expression and alterations in estrogen and androgen signaling. Conclusions: Thus, we integrated germline, somatic and clinical data to identify associations between genetically predicted lifelong liability to higher BMI and endometrial cancer tumor molecular features. These associations inform our understanding of how high BMI may influence the development of this cancer, shaping endometrial tumor biology differentially over the long term.<\/jats:p>","DOI":"10.3390\/genes17070744","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:58:04Z","timestamp":1782799084000},"page":"744","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Tumor Multi-Omic Landscape of Endometrial Cancers Developed on a Background of Adiposity"],"prefix":"10.3390","volume":"17","author":[{"given":"George","family":"Richenberg","sequence":"first","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Cancer Epidemiology and Prevention Research Unit, School of Public Health, Imperial College London, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Francis","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina N.","family":"Owen","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Bristol Cancer Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol BS1 3NU, UK"},{"name":"Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Gray","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK"},{"name":"North Wales Medical School, Bangor University, Bangor LL57 2DG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Robinson","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Bristol Cancer Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol BS1 3NU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lie A. G.","family":"Gabriel","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Branch, International Agency for Research on Cancer\/World Health Organization (IARC\/WHO), 69372 Lyon, France"},{"name":"Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Lawrenson","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma J.","family":"Davidson","sequence":"additional","affiliation":[{"name":"Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK"},{"name":"Department of Obstetrics and Gynaecology, St. Mary\u2019s Hospital, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joellen M.","family":"Schildkraut","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Mckay","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Branch, International Agency for Research on Cancer\/World Health Organization (IARC\/WHO), 69372 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom R.","family":"Gaunt","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline L.","family":"Relton","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK"},{"name":"London School of Hygiene and Tropical Medicine, University of London, London WC1E 7HT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8917-7384","authenticated-orcid":false,"given":"Emma E.","family":"Vincent","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2314-1426","authenticated-orcid":false,"given":"Siddhartha P.","family":"Kar","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK"},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK"},{"name":"The Li Ka Shing Early Cancer Institute, University of Cambridge, Cambridge CB2 0XZ, UK"},{"name":"Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK"},{"name":"Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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