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. 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

D Leongamornlert  1 , E Saunders  1 , T Dadaev  1 , M Tymrakiewicz  1 , C Goh  1 , S Jugurnauth-Little  1 , I Kozarewa  2 , K Fenwick  2 , I Assiotis  2 , D Barrowdale  3 , K Govindasami  1 , M Guy  1 , E Sawyer  1 , R Wilkinson  1 ; UKGPCS Collaborators; A C Antoniou  3 , R Eeles  4 , Z Kote-Jarai  1
Affiliations

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

D Leongamornlert et al. Br J Cancer. .

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.

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Figures

Figure 1
Figure 1
Average read coverage per gene. The 22 genes are shown along the x axis and the average sequencing coverage is shown along the y axis. All genes except STK11 had over 150x median coverage, and even STK11 coverage was above the required 20x.
Figure 2
Figure 2
Proportion of LoF mutations by gene. Proportion of the genes contributing to the 14 LoF identified in this study.
See this image and copyright information in PMC

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