Abstract C077: Germline pathogenic variant profiling of DNA double-strand break repair pathways in populations with African and European genetic ancestry

Abstract Background: African Americans (AAs) have higher incidence rates of advanced lung cancer when compared to European Americans (EAs). DNA double-strand breaks (DNA DSBs) are the major cause of genomic instability that initiates cancer. Our previous work found AA lung cancer patients have more germline DNA DSB repair deficiencies than EAs, suggesting unrelated AAs may share genomic risk factors for developing lung cancer. We hypothesize African ancestry drives disease-causing alterations in DNA DSB repair pathway genes. Methods: ClinVar criteria were used to profile germline pathogenic variants (PVs) across the four major DNA DSB repair pathways: homologous recombination repair (HRR), classical non-homologous end joining (c-NHEJ), alternative end-joining (alt-EJ), and single-strand annealing (SSA). The discovery cohort consisted of populations of African (n=37,545) and European (n=622,057) descent in the Genome Aggregation Database. The validation cohort included study participants in the NIH All of Us Research Program (African, n=50,080) and (European, n=125,860). In silico RNA (SpliceA1, Pangolin, and PhyloP) and protein (VEP and CADD) annotation tools were used to predict functional consequences. Results: In the African ancestry populations, 20 PVs across eight HRR genes, nine PVs across six c-NHEJ genes, six PVs across three alt-EJ genes, and 14 PVs across five SSA genes we discovered. In comparison, 115 PVs across 11 HRR genes, 52 PVs across eight c-NHEJ genes, 43 PVs across six alt-EJ genes, and 113 PVs across seven SSA genes were observed in the European ancestry populations. Interestingly, a RAD51 PV was exclusively enriched in African ancestry and not European ancestry populations for the HRR pathway. By contrast, NHEJ1, EXO1 and DCLRE1C PVs were uniquely present in those with European ancestry and not in individuals with African ancestry for the alt-EJ and SSA pathways, respectively. Frameshift mutations were the most common functional protein change in both populations. Conclusion: A total of 32 germline PVs across 13 DNA DSB repair genes were observed in African ancestry populations only, suggesting genetic ancestry may drive DNA repair deficiencies that increase susceptibility to developing lung cancer. Citation Format: Musinu Zakari, Egbenoma A. Aigboeghian, Khadijah A. Mitchell. Germline pathogenic variant profiling of DNA double-strand break repair pathways in populations with African and European genetic ancestry [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C077.