Abstract A007: Beyond continental ancestry categories: trans-population genomic similarity continuum reveals overlooked somatic-germline interactions across cancer types

Abstract A growing body of research highlighted a strong presence of continuums that describe human genomic diversity. Historical scholarship has also extensively investigated the use of discrete classification systems in human genomics further questioning their validity. To investigate the limiting effect of pre-defined stratification, we performed a wide comparative driver GWAS analysis at the trans-population (i.e. without stratification) vs continent-based population levels across 16 cancer types. Results demonstrate that in the MSK-IMPACT cohort (n = 56,826 samples), the analysis of the trans-population genomic similarity continuum captures significant somatic-germline interactions (p < 5x10-8) in cancer type-specific and pancancer cohorts, with a set of interactions overlooked by the discrete continent-based paradigm. We demonstrate that overlooked germline SNPs have similar allele frequencies and directional relationships with somatic alterations across pre-defined discrete categories, and that earlier stratification prevents their detection due to lowered statistical power. PheWAS analysis of detected germline variants revealed associations with cancer and non-cancer phenotypes reported in previous studies as well as novel hits. To expand the scope of the trans-population lens, we carried out a comparative analysis on 17 whole-exome TCGA cohorts to identify potential cancer drivers based on mutational frequencies. Results similarly revealed known and potential cancer drivers at the trans-population level that would be overlooked when pre-defined continent-based stratification is applied. The lens we adopt further highlights the necessity for new quantitative perspectives to comprehensively detect genomic patterns and to leverage entire genomic datasets without pre-defined stratification schemes. Citation Format: Hussein Mohsen, Tomin Perea-Chamblee, Jian Carrot-Zhang. Beyond continental ancestry categories: trans-population genomic similarity continuum reveals overlooked somatic-germline interactions across cancer types [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 A007.