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Br J Cancer. 2014 Mar 18;110(6):1663-72. doi: 10.1038/bjc.2014.30. Epub 2014 Feb 20.

Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease.

Author information

1
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
2
Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK.
3
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
4
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.

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.

PMID:
24556621
PMCID:
PMC3960610
DOI:
10.1038/bjc.2014.30
[Indexed for MEDLINE]
Free PMC Article

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