title: Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease.
abstract: BACKGROUND
  Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and among the leading causes of cancer-related death. The purpose of this study was to use second-generation sequencing technology to assess the frequency of deleterious mutations in 22 tumour suppressor genes in familial PrCa and estimate the relative risk of PrCa if these genes are mutated.
  
  
  METHODS
  Germline DNA samples from 191 men with 3 or more cases of PrCa in their family were sequenced for 22 tumour suppressor genes using Agilent target enrichment and Illumina technology. Analysis for genetic variation was carried out by using a pipeline consisting of BWA, Genome Analysis Toolkit (GATK) and ANNOVAR. Clinical features were correlated with mutation status using standard statistical tests. Modified segregation analysis was used to determine the relative risk of PrCa conferred by the putative loss-of-function (LoF) mutations identified.
  
  
  RESULTS
  We discovered 14 putative LoF mutations in 191 samples (7.3%) and these mutations were more frequently associated with nodal involvement, metastasis or T4 tumour stage (P=0.00164). Segregation analysis of probands with European ancestry estimated that LoF mutations in any of the studied genes confer a relative risk of PrCa of 1.94 (95% CI: 1.56-2.42).
  
  
  CONCLUSIONS
  These findings show that LoF mutations in DNA repair pathway genes predispose to familial PrCa and advanced disease and therefore warrants further investigation. The clinical utility of these findings will become increasingly important as targeted screening and therapies become more widespread.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: D
authors.initials: D
authors.lastname: Leongamornlert
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: E
authors.initials: E
authors.lastname: Saunders
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: T
authors.initials: T
authors.lastname: Dadaev
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: M
authors.initials: M
authors.lastname: Tymrakiewicz
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: C
authors.initials: C
authors.lastname: Goh
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: S
authors.initials: S
authors.lastname: Jugurnauth-Little
authors.affiliation: Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: I
authors.initials: I
authors.lastname: Kozarewa
authors.affiliation: Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: K
authors.initials: K
authors.lastname: Fenwick
authors.affiliation: Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: I
authors.initials: I
authors.lastname: Assiotis
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
authors.forename: D
authors.initials: D
authors.lastname: Barrowdale
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: K
authors.initials: K
authors.lastname: Govindasami
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: M
authors.initials: M
authors.lastname: Guy
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: E
authors.initials: E
authors.lastname: Sawyer
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: R
authors.initials: R
authors.lastname: Wilkinson
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Antoniou
authors.affiliation: 1] Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK [2] The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.
authors.forename: R
authors.initials: R
authors.lastname: Eeles
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Kote-Jarai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004260:DNA Repair; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics*; D012306:Risk