The tumor multi-omic landscape of endometrial cancers developed on a germline genetic background of adiposity

High body mass index (BMI) is a causal risk factor for endometrial cancer but the tumor molecular mechanisms affected by adiposity and their therapeutic relevance remain poorly understood. Here we characterize the tumor multi-omic landscape of endometrial cancers that have developed on a background of lifelong germline genetic exposure to elevated BMI. 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 life-course 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. High BMI germline PGS was associated with (i) upregulated tumor gene expression in the IL6 - JAK - STAT3 pathway (FDR=4.2×10−7); (ii) increased estimated intra-tumor activated mast cell infiltration (FDR=0.008); (iii) increased single base substitution (SBS) mutational signatures 1 (FDR=0.03) and 5 (FDR=0.09) and decreased SBS13 (FDR=0.09), implicating age-related and APOBEC mutagenesis, respectively; and (iv) decreased tumor EGFR protein expression (FDR=0.07). Alterations in IL6 - JAK - STAT3 signaling gene and EGFR protein expression were, in turn, significantly associated with both overall survival and progression-free interval. Thus, we integrated germline and somatic data using a novel study design to identify associations between genetically predicted lifelong exposure to higher BMI and potentially actionable endometrial cancer tumor molecular features. These associations inform our understanding of how high BMI may influence the development and progression of this cancer, impacting endometrial tumor biology and clinical outcomes. ### Competing Interest Statement Timothy Robinson reports funding for conference attendance from MSD and for educational workshops from Daiichi-Sanko. Tom R. Gaunt receives funding from Biogen and GSK for unrelated research. ### Funding Statement GR and AF are supported by Cancer Research UK [grant number C18281/A30905]. VG and SPK are supported by a UK Research and Innovation Future Leaders Fellowship to SPK [grant number MR/T043202/1]. KL, JMS, and SPK also receive support from the US National Institutes of Health (grant numbers R01CA211574 and R01CA259058). TR is supported by a UK National Institute for Health and Care Research (NIHR) Development and Skills Enhancement Award (grant number NIHR302363). EJC is supported by a NIHR Advanced Fellowship (grant number NIHR300650) and the NIHR Manchester Biomedical Research Centre (grant number NIHR203308). TRG is supported by the Medical Research Council Integrative Epidemiology Unit (grant number MC\_UU\_00032/03). EEV is supported by Diabetes UK [grant number 17/0005587] and the World Cancer Research Fund (WCRF, UK), as part of the WCRF International Grant Programme [grant number IIG\_2019\_2009]. TR, TRG, CLR and EEV are supported by Cancer Research UK [grant number C18281/A29019]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: , , , , , and I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data referred to in the manuscript are available at , , , , , and