Abstract A006: Increased germline mutational burden in individuals of African ancestry: Implications for interpretation of tumor mutation burden
Authors: Don Janith , Byron Sara A. , Zhang Guangfa , Izatt Tyler , Zhang Jiaming , Davis Bethany , Turner Bryce , Keats Jonathan J. , Trent Jeffrey M. , Rodriguez-Rodriguez Lorna , Schork Nicholas J. 
Published: January 2023

Introduction: Tumor mutation burden (TMB), defined as the number of somatic gene mutations per megabase in a tumor genome, is used clinically to identify cancer patients that may respond to immune checkpoint inhibitors. Recent studies suggest that patient ancestry can influence TMB, where individuals of African ancestry were found to have elevated TMB values based on tumor-only sequencing analysis. However, the impact of patient ancestry on germline mutational burden and implications for interpretation of tumor-only mutational burden data is largely unexplored. Methods: We examined the influence of patient ancestry on germline and tumor mutation burden using tumor-normal whole exome sequencing (WES) data from a pan-cancer cohort of 1228 individuals from a single institution. Genetic ancestry was estimated from constitutional WES data using single nucleotide polymorphism weights from external reference panels. Variant calling was performed using constitutional, tumor-only, and paired tumor-normal workflows. Total and loss-of-function burden scores were calculated for each participant from each workflow based on the total number of mutations detected in each sample and the total number of predicted loss-of-function mutations, based on snpEff annotations, respectively. Results: Genetic ancestry analysis found that one-third of this pan-cancer cohort was of non-European ancestry. 9.4% of individuals were of Eastern Asian ancestry, 5.3% of African ancestry, 1.0% of South Asian ancestry, 0.2% of Native American ancestry, and 17.1% of admixed ancestry, predominantly European and Native American admixed ancestry (15.6%). Total and loss-of-function germline burden scores varied across ancestral groups, with individuals of African ancestry showing significantly increased germline burden scores compared to other ancestral groups (p&lt;0.0001). Tumor-only analysis also showed increased mutation burden for individuals of African ancestry. However, when private and rare germline variation was taken into account using paired tumor-normal analysis, tumor mutation burden did not differ based on patient ancestry, suggesting the differences seen in tumor-only analysis are due to germline variation rather than differences in true somatic mutation burden. Conclusion: Our study reveals that the paucity of knowledge of ancestry-specific reference genomes leads to unacceptable health disparities in cancer, specifically in patients with African ancestry. We show that germline mutational burden varies by ancestral background, with individuals of African ancestry displaying increased genetic variation compared to other ancestral populations. These results suggest that patient ancestry should be considered when interpreting tumor mutational burden values, particularly from tumor-only analysis. Approaches utilizing paired tumor-normal analysis or ancestry-specific reference genomes can aid in more accurate assessment of TMB, thereby avoiding futile treatments targeted at presumed high mutational burden tumors specifically in African American populations.

Citation Format: Janith Don, Sara A. Byron, Guangfa Zhang, Tyler Izatt, Jiaming Zhang, Bethany Davis, Bryce Turner, Jonathan J. Keats, Jeffrey M. Trent, Lorna Rodriguez-Rodriguez, Nicholas J. Schork. Increased germline mutational burden in individuals of African ancestry: Implications for interpretation of tumor mutation burden [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A006.