Two-stage study of familial prostate cancer by whole-exome sequencing and custom capture identifies 10 novel genes associated with the risk of prostate cancer

<strong>Background:</strong> Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease.<p></p> <p><strong>Objective:</strong> To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa.</p> <p><strong>Design, setting, and participants:</strong> A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls.</p> <p><strong>Outcome measurements and statistical analysis:</strong> Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls.</p> <p><strong>Results and limitations:</strong> Eleven genes previously reported to be associated with PCa were detected (<i>ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3</i>, and <i>TERT</i>), as well as an additional 10 novel genes (<i>PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7</i>, and <i>THAP3</i>). Of these 10 novel genes, all but <i>PABPC1</i> and <i>ULK4</i> were primarily associated with the risk of aggressive PCa.</p> <p><strong>Conclusions:</strong> Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease.</p> <p><strong>Patient summary:</strong> Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.</p>