title: Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Sally M
authors.initials: SM
authors.lastname: Hunter
authors.affiliation: Centre for Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Rowley
authors.affiliation: Tissupath, Mt Waverley, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Clouston
authors.affiliation: Bioinformatics Core Facility, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: Bioinformatics Core Facility, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Lupat
authors.affiliation: kConFab Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Department of Urology, Austin Hospital, University of Melbourne, Heidelberg, Australia.
authors.forename: Nishanth
authors.initials: N
authors.lastname: Krishnananthan
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
authors.forename: Gail
authors.initials: G
authors.lastname: Risbridger
authors.affiliation: Department of Physiology, Monash University, Clayton, Australia.
authors.forename: Renea
authors.initials: R
authors.lastname: Taylor
authors.affiliation: Department of Urology, Austin Hospital, University of Melbourne, Heidelberg, Australia.
authors.forename: Damien
authors.initials: D
authors.lastname: Bolton
authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
authors.affiliation: kConFab Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia. Electronic address: heather.thorne@petermac.org.
authors.forename: Heather
authors.initials: H
authors.lastname: Thorne
mesh_terms: D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D010375:Pedigree; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor
keywords: Exome sequencing; Gene variants; Prostate cancer