Abstract
In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs (N = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes (RAD51, RAD54L, RAD54B), which are potentially targetable, as well as PMS2 and BRCA1, are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients.
Highlights
In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease
Genomic DNA specimens were derived from blood samples collected from active duty and retired military personnel treated with radical prostatectomy (RP) at the Walter Reed National Military Medical Center (WRNMMC) and archived at the Center for Prostate Disease Research (CPDR) biospecimen bank[19]
23 DDRGs were mutated in AA patients (N = 259), which is about three times more than what was reported in similar recent studies[12,13,39,40]
Summary
In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. We profile germline mutations in all known DDRGs (N = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. We have developed foundational data by evaluating the complete spectrum and prevalence of germline mutations in all known DDRGs in both AA and EA CaP patients who had equal access to screening, treatment, and follow-up These data may aid in future goals of personalized medicine by enhancing the stratification of patients for targeted therapeutic options and by providing genetic counseling, to highrisk families
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