Abstract A006: Increased germline mutational burden in individuals of African ancestry: Implications for interpretation of tumor mutation burden

• Published in: Cancer epidemiology, biomarkers & prevention biomarkers & prevention, 2023-01, Vol.32 (1_Supplement), p.A006-A006
• Main 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.
• Format: Article
• Language: English
• ISSN: 1538-7755; 1538-7755
• DOI: 10.1158/1538-7755.DISP22-A006

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