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

Autor: Richenberg G; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Francis A; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Owen CN; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.; Bristol Cancer Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK., Gray V; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Robinson T; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.; Bristol Cancer Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK., Gabriel AA; Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland., Lawrenson K; Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Crosbie EJ; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.; Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust, St. Mary's Hospital, Manchester, UK., Schildkraut JM; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA., Mckay JD; Genomic Epidemiology Branch, International Agency for Research on Cancer/World Health Organization (IARC/WHO), Lyon, France., Gaunt TR; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Relton CL; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Vincent EE; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Kar SP; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.; Early Cancer Institute, University of Cambridge, Cambridge, UK.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2023 Oct 10. Date of Electronic Publication: 2023 Oct 10.
DOI: 10.1101/2023.10.09.23296765
Abstrakt: 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.
Databáze: MEDLINE