10505 Background: Inherited defects in DNA damage repair (DDR) genes (e.g. ATM, BRCA1/2) and the tumor suppresser gene HOXB13 are rare in the general population, but have been observed at a higher rate among men with early-onset and advanced prostate cancer. However, most studies include few, if any, African American men, highlighting the need to understand the contribution of mutations in these genes in this high-risk population. Methods: A population-based cohort of 757 African American men diagnosed with prostate cancer at age 62 years or younger were identified and enrolled through the Metropolitan Detroit Cancer Surveillance System (MDCSS), one of NCI’s founding members of the SEER program. Participants completed a short survey to collect information on family history, medical history (including cancer-related treatment), surveillance, and health behaviors. Each participant submitted a saliva or blood sample for genetic analyses and consent for tumor tissue if available. All clinical data were collected through linkage with the MDCSS registry. Full exome sequencing was performed and herein, we report the mutation patterns observed in a panel of DNA repair genes and HOXB13. All variants were ranked according to frequency (MAF < 1%); REVEL, SIFT and PolyPhen scores for pathogenic potential; evidence from existing literature; and prevalence in the cohort. Results: Among the 744 African American prostate cancer cases with adequate DNA for sequencing and thus included in this analysis, the mean age at diagnosis was 55.6 years, 29% reported a family history of prostate cancer in a first degree family member, and 40% were initially diagnosed with intermediate- to high-risk disease (stage T3/T4 and/or Gleason 4+3 and higher at diagnosis). We identified 20 variants that were either known or predicted to be pathogenic in 11 candidate genes ( ATM, ATR, BRCA1/2, BRIP1, CHEK2, FANCA, HOXB13, MSH2, PALB2, and PMS2). These particular variants were more common among men diagnosed before age 55 and in men with high grade cancer in this cohort. Conclusions: Our results suggest that mutations in DDR genes and HOXB13 may be important cancer risk factors for African American men diagnosed with early-onset and intermediate- to high-risk disease. Further study is necessary to describe the spectrum and prevalence of genetic mutations in this population including the characterization of variants of unknown significance.
Rare germline mutations in African American men diagnosed with early‐onset prostate cancer
