1. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease
- Author
-
Antonis C. Antoniou, S Jugurnauth-Little, Ed Saunders, Zsofia Kote-Jarai, Malgorzata Tymrakiewicz, Iwanka Kozarewa, Rosemary A. Wilkinson, Michelle Guy, Tokhir Dadaev, Chee L. Goh, Koveela Govindasami, Kerry Fenwick, Daniel Leongamornlert, Daniel Barrowdale, Rosalind A. Eeles, Emma J. Sawyer, and Ioannis Assiotis
- Subjects
Proband ,Adult ,Male ,Risk ,Cancer Research ,DNA Repair ,DNA repair ,Biology ,medicine.disease_cause ,urologic and male genital diseases ,Germline ,Familial prostate cancer ,Germline mutation ,Genetic variation ,medicine ,Humans ,Genetic Predisposition to Disease ,familial prostate cancer ,DNA repair gene mutations ,Gene ,Germ-Line Mutation ,Aged ,Genetics ,Aged, 80 and over ,Mutation ,Prostatic Neoplasms ,Genetics and Genomics ,Middle Aged ,relative risk ,Oncology ,next-generation sequencing - 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.
- Published
- 2013