Abstract 2074: Germline mutation landscape of all DNA repair genes in African American prostate cancer patients

Abstract

Abstract Introduction: DNA damage repair genes (DDRGs) play a critical role in genomic stability and their dysfunction contributes to mutagenesis in several cancer types. In prostate cancer (CaP) emerging data provide potential roles of DDR pathways in aggressive disease. However, the association with disease progression and therapeutic stratification based on inherited mutations of DDRGs remains to be defined in African American (AA) CaP patients. Our objective was to genomically profile all known annotated DDRGs in AA and Caucasian American (CA) CaP patient to determine whether DDRG germline variation status can refine patient stratification for targeted therapeutic options. Methods: Germline mutations in all DDRGs (N=276) was evaluated by whole genome sequence (WGS) analysis of archived blood DNA samples from 600 CaP 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 (PCA) was used infer axes of genetic variation within AA men and examine individual and population clustering to predict ancestry of each sample using the Peddy program. Variant frequencies in CPDR CaP patients were compared to variant frequencies available from the Exome Aggregation Consortium (ExAC) control cases with no CaP by Fisher's Exact Test, using false discovery rate adjusted p-values. Results: Interrogation of the complete known DDRG set of 276 genes revealed several known and novel mutations in this cohort. The Pathogenic/likely pathogenic (P/LP) variant carrier rate was higher than reported before (23.5%) in both AA and CA patients. However, the analysis revealed that more than 2/3 of the identified 47 DDRGs with P/LP mutation were different between AA and CA patients. Unlike in CA patients, several RAD family genes (RAD51, RAD54L, RAD54B), PMS2, and BRCA1 were among the most frequently mutated DDRGs in AA patients, but not in CA patients. The most frequent (over 1% carrier frequency) and potentially targetable type of mutations were independently validated by ddPCR. These genes are part of targetable DDRG pathways (homologous recombination and mismatch repair), suggesting that targeted therapy could potentially benefit AA patients. AA men harbor more potentially targetable DDRG germline mutations (over 10%) than CA men which may contribute to addressing CaP disparity. Germline mutations in any of the DDRG genes was associated with shorter time to BCR (Kaplan-Meier analysis, log rank p value 0.044) in AA patients, but not in CA patients. Conclusion: Our findings highlight distinct racial differences in DDRGs and addresses the clinical utility by targeted therapy across AA and CA men. The percentage of patients with DDRG germline variation is of suitable threshold (23%) to consider early genetic testing for them in both AA and CA patients. Citation Format: Indu Kohaar, Xijun Zhang, Shyh-Han Tan, Darryl Nousome, Kevin Babcock, Lakshmi Ravindranath, Gauthaman Sukumar, Elisa Mcgrath-Martinez, John Rosenberger, Camille Alba, Amina Ali, Denise Young, Yongmei Chen, Jennifer Cullen, Inger Rosner, Isabella Sesterhenn, Albert Dobi, Gregory Chesnut, Clesson Turner, Clifton Dalgard, Matthew Wilkerson, Shiv Srivastava, Gyorgy Petrovics. Germline mutation landscape of all DNA repair genes in African American prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2074.