Abstract C163: Interaction of germline genetic variation and environmental factors in endometrial cancer prevalence in a population biobank
Authors: Founta Kyriaki , Qi Yuewen , Chambwe Nyasha 
Published: September 2024

Despite an overall general decline in cancer mortality over the last two decades, endometrial cancer (EC) is increasing in both incidence and mortality globally. In addition, EC has one of the largest racial disparities in mortality, most attributed to Black women being more likely to present with the more aggressive histological subtypes that are harder to diagnose and patients presenting at later stages when they are likely to have worse outcomes. While it is known that there are genetic and environmental factors that contribute to this observed disparity, we have a limited understanding of how these factors interact to jointly determine the prevalence of EC and/or result in worst outcomes in women who self-identify as Black or African American. To gain a better understanding of factors associated with EC prevalence in racially diverse women as defined either using self-identified race/ethnicity and by genetic ancestry, we used data from the National Institutes of Health All of Us Research Program to define an EC case control cohort based on electronic health record and survey information and the availability of whole genome sequencing (WGS) data for the same program participants. We mined the genetic data to identifier carriers of pathogenic or likely pathogenic mutations in known EC predisposition syndrome genes such as Lynch syndrome and across the genome broadly. Using data from the All of Us Social Determinants of Health survey, we calculated individual-level measures that characterize the neighborhood-built environment (neighborhood physical and social disorder, walkability, crime, and residential density) and the neighborhood social environment (social cohesion and support, perceived discrimination, and stress). Linear regression models examined the associations between genetic predisposition and neighborhood social and built environments independently and jointly with endometrial cancer prevalence. Our provisional results show that EC cases are 100 times more likely to carry pathogenic or likely pathogenic germline genetic variants compared to controls and that neighborhood social and built environment factors are associated with EC incidence. Models incorporating both genetic and measures of the social and built environments show complex relationships that warrant further exploration. While we find evidence of pathogenic and likely pathogenic variants associated with EC incidence, our studies remain underpowered due to the size and the continued underrepresentation of black of African American women in study cohorts and the relatively low minor allele frequencies of likely pathogenic variants in the general population. Larger racially and ethnically diverse study cohorts that measure both genetic and non-genetic factors in the same study populations are sorely needed to better characterize the relative contribution of genetics and environmental factors in EC prevalence and ultimately to address the rising global health challenge of EC disparities.

Citation Format: Kyriaki Founta, Yuewen Qi, Nyasha Chambwe. Interaction of germline genetic variation and environmental factors in endometrial cancer prevalence in a population biobank [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C163.