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
: Daniel J.Schaid, Shannon K. McDonnell, Liesel M. FitzGerald, Lissa DeRycke, Zachary Fogarty, Graham G.Giles, Robert J. MacInnis, Melissa C.Southey, Tu Nguyen-Dumont, Geraldine Cancel-Tassin, Oliver Cussenot, Alice S.Whittemore, Weiva Sieh, Nilah Monnier Ioannidis, Chih-Lin Hsieh, Janet L. Stanford, Johanna Schleutker, Cheryl D. Cropp, John Carpten, Josef Hoegel, Rosalind Eeles, Zsofia Kote-Jarai, Michael J.Ackerman, Christopher J.Klein, Diptasri Mandal, Kathleen A.Cooney, Joan E.Bailey-Wilson, Brian Helfand, William J.Catalona, Fredrick Wiklund, Shaun Riska, Saurabh Bahetti,Melissa C.Larson, Lisa Cannon Albright, Craig Teerlink, Jianfeng Xu, William Isaacs, Elaine A.Ostrander, Stephen N.Thibodeau
Publisher: Karger
: 2021
: European Urology
: European urology
: Eur Urol
: 0302-2838
: 1873-7560
DOI: https://doi.org/10.1016/j.eururo.2020.07.038
Background: Family history of prostate cancer (PCa) is a well-known risk factor, and bothcommon and rare genetic variants are associated with the disease.Objective: To detect new genetic variants associated with PCa, capitalizing on the role offamily history and more aggressive PCa.Design, setting, and participants: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with astrong family history of disease or with more aggressive disease (491 cases and429 controls). Aggressive disease was based on a sum of scores for Gleason score, nodestatus, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recur-rence, and time to PCa death. Genes identified in stage one were screened in stage twousing a custom-capture design in an independent set of 2917 cases and 1899 controls.Outcome measurements and statistical analysis: Frequencies of genetic variants (singlyor jointly in a gene) were compared between cases and controls.Results and limitations: Eleven genes previously reported to be associated with PCawere detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3,and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6,MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all butPABPC1 and ULK4 were primarily associated with the risk of aggressive PCa.Conclusions: Our approach demonstrates the advantage of gene sequencing in thesearch for genetic variants associated with PCa and the benefits of sampling patientswith a strong family history of disease or an aggressive form of disease.Patient summary: Multiple genes are associated with prostate cancer (PCa) among menwith a strong family history of this disease or among men with an aggressive form of PCa.