Abstract B054: Inherited mutations of DNA damage repair genes in a racially diverse cohort of men with prostate cancer
Authors: Kohaar Indu , Zhang Xijun , Chesnut Gregory , Dalgard Clifton , Wilkerson Matthew D. , Petrovics Gyorgy 
Published: June 2023

Introduction: DNA damage repair genes (DDRGs) play an important role in genomic stability and mutations in DDRGs contribute to clinically significant prostate cancer (PCa). However, the association of germline mutations in DDRGs with PCa progression and therapeutic stratification remain to be defined in African American (AA) men. Our objective was to genomically profile all known DDRGs and provide ancestry specific findings, focusing on PCa patients with African ancestry. Methods: Germline mutations in all DDRGs (N=276) was evaluated by whole genome sequence (WGS) analysis of archived blood DNA samples from 600 PCa patients (300 AA and 300 CA) who underwent primary treatment at Walter Reed National Military Medical Center. The WGS mean coverage exceeded 37x. Principal Component Analysis using the Peddy program was conducted, and ancestry prediction was based on a machine learning approach using 1000G as reference. Variant frequencies in CPDR PCa patients were compared to variant frequencies available from the Exome Aggregation Consortium (ExAC) controls with no PCa. Data analysis approaches included single variant association, gene-based total frequency test and clinico-pathological associations for germline mutations. All statistical tests were two-sided, and FDR adjusted. FDR &lt; 0.05 was set as significance threshold. Results: Comprehensive analysis of 276 DDRGs revealed that germline mutation (Pathogenic/Likely Pathogenic; P/LP) carrier rate was 23.5%, which is three times higher than reported before in both AA and CA men, due to our unbiased WGS approach. We found that only 13 of the 46 DDRGs identified with P/LP mutations were common to AA and CA men, demonstrating clear disparity along ancestry lines. Importantly, RAD family genes (RAD54L, RAD54B, RAD51), which are potentially targetable, as well as PMS2 and BRCA1, were among the most frequently mutated DDRGs in AA, but not in CA men. Germline mutations in RAD51 and PMS2 were enriched in AA cohort as compared to CA men (P 0.01 and 0.03 respectively), while germline mutations in FANCA were significantly enriched in CA cohort (P &lt; 0.01). Pathway analysis showed that the HR pathway (with 15 mutations) was associated with faster disease progression to biochemical recurrence (BCR) (P &lt;0.05), while the NHEJ pathway (with three mutations) was found to be marginally associated with metastasis (p &lt;0.05). Additionally, we found that germline mutations in DDRGs was associated with shorter time to BCR (P &lt;0.05) in AA patients, but not in CA men. Conclusion: Our findings highlight distinct DDRG germline mutation profile across AA and CA prostate cancer men. This may help refine patient stratification for specific targeted therapeutic options especially for under-studied AA men. Future replication studies in an independent patient cohort are warranted to validate our findings.

Citation Format: Indu Kohaar, Xijun Zhang, Gregory Chesnut, Clifton Dalgard, Matthew D. Wilkerson, Gyorgy Petrovics. Inherited mutations of DNA damage repair genes in a racially diverse cohort of men with prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B054.