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

• Type of Material: Article
• Authors: George Richenberg, University of Bristol; Amy Francis, University of Bristol; Carina N. Owen, University of Bristol; Victoria Gray, University of Bristol; Timothy Robinson, University of Bristol; Aurélie AG Gabriel, University of Lausanne; Kate Lawrenson, Cedars-Sinai Medical Center; Emma J. Crosbie, University of Manchester; Joellen Martha Schildkraut, Emory University; james D. Mckay, International Agency for Research on Cancer/World Health Organization; Tom R. Gaunt, University of Bristol; Caroline L. Relton, University of Bristol; Emma E. Vincent, University of Bristol; Siddhartha P. Kar, University of Bristol
• Language: English
• Date: 2023-10-10
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1101/2023.10.09.23296765
• Title of Journal or Parent Work: medRxiv
• Start Page: 23296765
• Grant/Funding Information: 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].
• Keywords: The Cancer Genome Atlas; polygenic score; High body mass index
• Research Categories: Health Sciences, Oncology

Abstract

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.