The Tumor Multi-Omic Landscape of Endometrial Cancers Developed on a Background of Adiposity
Year: 2026
Type: article
Abstract: Background: High body mass index (BMI) is a causal risk factor for endometrial cancer, but the tumor molecular mechanisms affected by adiposity remain poorly understood. 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 × 10−7) 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.
Source: Genes
Institutions: University of Bristol, MRC Integrative Epidemiology Unit, Imperial College London, University Hospitals Bristol and Weston NHS Foundation Trust, Cardiff University, Bangor University, University of Geneva, World Health Organization, Centre international de recherche sur le cancer, The University of Texas at San Antonio Health Science Center, Manchester Academic Health Science Centre, University of Manchester, St Mary's Hospital, Manchester University NHS Foundation Trust, Emory University, University of London, London School of Hygiene & Tropical Medicine, University of Cambridge
Language: English
Topic: Cancer Risks and Factors
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,137
Awards: G1483213741, Genomic and Transcriptomic Analysis of Breast and Ovarian Cancers, G2477011702, G2960337771, The influence of cancer on people with Type 2 diabetes, G323433674, G336944243, Common biology underlying pleiotropic breast, prostate and ovarian cancer risk loci, G8277589319, NIHR Development and Skills Enhancement Award, G8530269906, Urine testing for cervical screening: is it effective and can it improve uptake?
OpenAlex ID: W7166686058