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Prostate. 2014 Oct;74(14):1371-8. doi: 10.1002/pros.22849. Epub 2014 Aug 11.

Mutational landscape of candidate genes in familial prostate cancer.

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  • 1Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.

Abstract

BACKGROUND:

Family history is a major risk factor for prostate cancer (PCa), suggesting a genetic component to the disease. However, traditional linkage and association studies have failed to fully elucidate the underlying genetic basis of familial PCa.

METHODS:

Here, we use a candidate gene approach to identify potential PCa susceptibility variants in whole exome sequencing data from familial PCa cases. Six hundred ninety-seven candidate genes were identified based on function, location near a known chromosome 17 linkage signal, and/or previous association with prostate or other cancers. Single nucleotide variants (SNVs) in these candidate genes were identified in whole exome sequence data from 33 PCa cases from 11 multiplex PCa families (3 cases/family).

RESULTS:

Overall, 4,856 candidate gene SNVs were identified, including 1,052 missense and 10 nonsense variants. Twenty missense variants were shared by all three family members in each family in which they were observed. Additionally, 15 missense variants were shared by two of three family members and predicted to be deleterious by five different algorithms. Four missense variants, BLM Gln123Arg, PARP2 Arg283Gln, LRCC46 Ala295Thr and KIF2B Pro91Leu, and one nonsense variant, CYP3A43 Arg441Ter, showed complete co-segregation with PCa status. Twelve additional variants displayed partial co-segregation with PCa.

CONCLUSIONS:

Forty-three nonsense and shared, missense variants were identified in our candidate genes. Further research is needed to determine the contribution of these variants to PCa susceptibility.

KEYWORDS:

exome sequencing; familial cancer; susceptibility

PMID:
25111073
PMCID:
PMC4142071
DOI:
10.1002/pros.22849
[PubMed - indexed for MEDLINE]
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