Abstract B075: Identification of shared DNA repair gene variants in the African American Hereditary Prostate Cancer (AAHPC) cohort using whole-exome sequencing

Abstract

African American men experience disproportionately higher incidence and mortality rates from prostate cancer yet remain underrepresented in genomic studies, limiting the discovery and validation of inherited susceptibility variants that contribute to hereditary prostate cancer (HPC) risk. Homologous recombination DNA repair genes, including BRCA2, BRIP1, and RAD51C, have established or emerging roles in hereditary cancer susceptibility but remain understudied in African American populations. We investigated shared inherited variants in these biologically relevant genes within the African American Hereditary Prostate Cancer (AAHPC) cohort, a well-characterized multi-site family-based cohort enriched for hereditary disease with families containing four or more men diagnosed with prostate cancer. We hypothesized that these genes would harbor recurrent inherited variants shared among affected members of AAHPC families. Whole-exome sequencing (WES) data from 101 affected men across 62 AAHPC families were jointly analyzed. Pedigree relationships were genetically validated before evaluating variants within 71 DNA repair genes, including BRCA2, BRIP1, and RAD51C, to identify shared inherited variants within and across families. Functional consequences were annotated using Ensembl Variant Effect Predictor (VEP) and dbNSFP. Functional impact scores were derived from more than 30 in silico annotation tools, normalized to a continuous scale from "Benign" (0) to "Damaging" (1), and summarized using mean and median consensus scores for variant prioritization. Preliminary findings show that 2,646 unique variants identified across BRCA2, BRIP1, and RAD51C, 888 variants were shared by at least two affected family members, and 596 variants were observed in two or more families. Forty-six variants were classified as damaging or possibly damaging based on aggregated functional prediction scores. Two recurrent variants in BRCA2 and BRIP1 demonstrated both high predicted functional impact and recurrence within and across families, prioritizing them as candidate HPC susceptibility variants. Our findings identify recurrent, potentially damaging DNA repair gene variants in the AAHPC cohort and expand knowledge of inherited prostate cancer susceptibility in African American families, a population historically underrepresented in genomic research. These findings support efforts to improve genomic representation in precision oncology research and provide a foundation for future whole-genome sequencing and segregation analyses to further characterize inherited prostate cancer risk. Kenyaita M. Hodge, Karl Opara, Sydni Kimble, Rick Kittles, Cheryl D. Cropp. Identification of shared DNA repair gene variants in the African American Hereditary Prostate Cancer (AAHPC) cohort using whole-exome sequencing [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr B075.