Mutational landscape of candidate genes in familial prostate cancer

Anna M. Johnson, Kimberly A. Zuhlke, Chris Plotts, Shannon K. McDonnell, Sumit Middha, Shaun M. Riska, Daniel J Schaid, Stephen N Thibodeau, Julie A. Douglas, Kathleen A. Cooney

Research output: Contribution to journalArticle

12 Citations (Scopus)

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). Result 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. Cconclusions 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. Prostate 74:1371-1378, 2014.

Original languageEnglish (US)
Pages (from-to)1371-1378
Number of pages8
JournalProstate
Volume74
Issue number14
DOIs
StatePublished - 2014

Fingerprint

Prostatic Neoplasms
Genes
Exome
Prostate
Nucleotides
Chromosomes, Human, Pair 17
Familial Prostate cancer
Research
Neoplasms

Keywords

  • exome sequencing
  • familial cancer
  • susceptibility

ASJC Scopus subject areas

  • Urology
  • Oncology

Cite this

Johnson, A. M., Zuhlke, K. A., Plotts, C., McDonnell, S. K., Middha, S., Riska, S. M., ... Cooney, K. A. (2014). Mutational landscape of candidate genes in familial prostate cancer. Prostate, 74(14), 1371-1378. https://doi.org/10.1002/pros.22849

Mutational landscape of candidate genes in familial prostate cancer. / Johnson, Anna M.; Zuhlke, Kimberly A.; Plotts, Chris; McDonnell, Shannon K.; Middha, Sumit; Riska, Shaun M.; Schaid, Daniel J; Thibodeau, Stephen N; Douglas, Julie A.; Cooney, Kathleen A.

In: Prostate, Vol. 74, No. 14, 2014, p. 1371-1378.

Research output: Contribution to journalArticle

Johnson, AM, Zuhlke, KA, Plotts, C, McDonnell, SK, Middha, S, Riska, SM, Schaid, DJ, Thibodeau, SN, Douglas, JA & Cooney, KA 2014, 'Mutational landscape of candidate genes in familial prostate cancer', Prostate, vol. 74, no. 14, pp. 1371-1378. https://doi.org/10.1002/pros.22849
Johnson AM, Zuhlke KA, Plotts C, McDonnell SK, Middha S, Riska SM et al. Mutational landscape of candidate genes in familial prostate cancer. Prostate. 2014;74(14):1371-1378. https://doi.org/10.1002/pros.22849
Johnson, Anna M. ; Zuhlke, Kimberly A. ; Plotts, Chris ; McDonnell, Shannon K. ; Middha, Sumit ; Riska, Shaun M. ; Schaid, Daniel J ; Thibodeau, Stephen N ; Douglas, Julie A. ; Cooney, Kathleen A. / Mutational landscape of candidate genes in familial prostate cancer. In: Prostate. 2014 ; Vol. 74, No. 14. pp. 1371-1378.
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N2 - 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). Result 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. Cconclusions 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. Prostate 74:1371-1378, 2014.

AB - 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). Result 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. Cconclusions 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. Prostate 74:1371-1378, 2014.

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