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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

Citation

Schaid, DJ and McDonnell, SK and Fitzgerald, LM and DeRycke, L and Fogarty, Z and Giles, GG and MacInnis, RJ and Southey, MC and Nguyen-Dumont, T and Cancel-Tassin, G and Cussenot, O and Whittemore, AS and Sieh, W and Ioannidis, NM and Hsieh, C-L and Stanford, JL and Schleutker, J and Cropp, CD and Carpten, J and Hoegel, J and Eeles, R and Kote-Jarai, Z and Ackerman, MJ and Klein, CJ and Mandal, D and Cooney, KA and Bailey-Wilson, JE and Helfand, B and Catalona, WJ and Wiklund, F and Riska, S and Bahetti, S and Larson, MC and Albright, LC and Teerlink, C and Xu, J and Isaacs, W and Ostrander, EA and Thibodeau, SN, 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, European Urology, 79, (3) pp. 353-361. ISSN 0302-2838 (2020) [Refereed Article]

Copyright Statement

Copyright 2020 European Association of Urology

DOI: doi:10.1016/j.eururo.2020.07.038

Abstract

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.

Item Details

Item Type:Refereed Article
Keywords:prostate cancer, exome sequencing, custom-capture sequencing, familial prostate cancer, genetic risk variants, whole-exome sequencing
Research Division:Biomedical and Clinical Sciences
Research Group:Oncology and carcinogenesis
Research Field:Cancer genetics
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Fitzgerald, LM (Dr Liesel Fitzgerald)
ID Code:140942
Year Published:2020
Deposited By:Menzies Institute for Medical Research
Deposited On:2020-09-15
Last Modified:2021-06-23
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