TY - JOUR
T1 - 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[Formula presented]
AU - Schaid, Daniel J.
AU - McDonnell, Shannon K.
AU - FitzGerald, Liesel M.
AU - DeRycke, Lissa
AU - Fogarty, Zachary
AU - Giles, Graham G.
AU - MacInnis, Robert J.
AU - Southey, Melissa C.
AU - Nguyen-Dumont, Tu
AU - Cancel-Tassin, Geraldine
AU - Cussenot, Oliver
AU - Whittemore, Alice S.
AU - Sieh, Weiva
AU - Ioannidis, Nilah Monnier
AU - Hsieh, Chih Lin
AU - Stanford, Janet L.
AU - Schleutker, Johanna
AU - Cropp, Cheryl D.
AU - Carpten, John
AU - Hoegel, Josef
AU - Eeles, Rosalind
AU - Kote-Jarai, Zsofia
AU - Ackerman, Michael J.
AU - Klein, Christopher J.
AU - Mandal, Diptasri
AU - Cooney, Kathleen A.
AU - Bailey-Wilson, Joan E.
AU - Helfand, Brian
AU - Catalona, William J.
AU - Wiklund, Fredrick
AU - Riska, Shaun
AU - Bahetti, Saurabh
AU - Larson, Melissa C.
AU - Cannon Albright, Lisa
AU - Teerlink, Craig
AU - Xu, Jianfeng
AU - Isaacs, William
AU - Ostrander, Elaine A.
AU - Thibodeau, Stephen N.
N1 - Publisher Copyright:
© 2020 European Association of Urology
PY - 2021/3
Y1 - 2021/3
N2 - Background: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. Objective: To detect new genetic variants associated with PCa, capitalizing on the role of family 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 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. Outcome measurements and statistical analysis: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. Results and limitations: Eleven genes previously reported to be associated with PCa were 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 but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. Conclusions: 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. Patient summary: 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.
AB - Background: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. Objective: To detect new genetic variants associated with PCa, capitalizing on the role of family 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 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. Outcome measurements and statistical analysis: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. Results and limitations: Eleven genes previously reported to be associated with PCa were 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 but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. Conclusions: 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. Patient summary: 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.
KW - Custom-capture sequencing
KW - Familial prostate cancer
KW - Genetic risk variants
KW - Whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85089367131&partnerID=8YFLogxK
U2 - 10.1016/j.eururo.2020.07.038
DO - 10.1016/j.eururo.2020.07.038
M3 - Article
C2 - 32800727
AN - SCOPUS:85089367131
SN - 0302-2838
VL - 79
SP - 353
EP - 361
JO - European Urology
JF - European Urology
IS - 3
ER -