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Title: Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer.
Austin Authors: Hunter, Sally M;Rowley, Simone M;Clouston, David;Li, Jason;Lupat, Richard;Krishnananthan, Nishanth;Risbridger, Gail;Taylor, Renea;Bolton, Damien M ;Campbell, Ian G;Thorne, Heather
Affiliation: Tissupath, Mt Waverley, Australia
Centre for Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Australia
Bioinformatics Core Facility, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
kConFab Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
Department of Urology, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
Department of Physiology, Monash University, Clayton, Australia
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
Issue Date: Mar-2016
Date: 2015-11-14
Publication information: Urologic oncology 2016; 34(3): 120.e9-16
Abstract: A family history of prostate cancer (PC) is a well-recognized high-risk factor for the development of clinically significant PC. To date, traditional linkage and association studies have identified only a limited number of genes and specific gene variants that account for only a small proportion of PC risk. To identify novel PC predisposition genes we performed whole-exome sequencing of PC-affected men from families with a significant history of PC. Exome sequencing was performed on 5 PC-affected men from 3 families where there were multiple cases of PCs and where diagnostic testing returned a negative result for BRCA1 and BRCA2 mutations. Genotyping was performed for all potentially predisposing variants detected within each family on the affected and unaffected male participants. Essential splice site, missense, and stop-lost variants were filtered against a recently published candidate gene list. A total of 19 truncating variants and 17 missense variants were identified for genotyping in all prostate-affected and unaffected male participants. In all, 3 missense variants, PCTP, MCRS1, and ATRIP, demonstrated complete segregation and 1 missense variant, PARP2, demonstrated partial segregation with PC. In addition, 3 truncating variants, CYP3A43, DOK3, and PLEKHH3, demonstrated complete segregation and 3 truncation mutations, HEATR5B, GPR124, and HKR1, demonstrated partial segregation with PC. No segregating variants between the 3 families were shared. In all, 10 truncating or missense variants showed either complete or partial segregation with PC in the relevant families. CYP3A43 and PARP2 variants have been shown to occur in other familial PCs and our findings add to the contribution that these variants potentially have in the risk and development of PC in BRCAX cases.
DOI: 10.1016/j.urolonc.2015.10.009
ORCID: 0000-0002-5145-6783
Journal: Urologic oncology
PubMed URL: 26585945
Type: Journal Article
Subjects: Exome sequencing
Gene variants
Prostate cancer
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