Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer

Sally M. Hunter, Simone M. Rowley, David Clouston, KCon Fab Investigators, Jason Li, Richard Lupat, Nishanth Krishnananthan, Gail Risbridger, Renea Taylor, Damien Bolton, Ian G. Campbell, Heather Thorne

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

OBJECTIVE: A family history of prostate cancer (PC) is a well-recognized high-risk factor for the development of clinically significant PC. To date, traditional linkage and association studies have identified only a limited number of genes and specific gene variants that account for only a small proportion of PC risk. To identify novel PC predisposition genes we performed whole-exome sequencing of PC-affected men from families with a significant history of PC. METHODS AND MATERIALS: Exome sequencing was performed on 5 PC-affected men from 3 families where there were multiple cases of PCs and where diagnostic testing returned a negative result for BRCA1 and BRCA2 mutations. Genotyping was performed for all potentially predisposing variants detected within each family on the affected and unaffected male participants. RESULTS: Essential splice site, missense, and stop-lost variants were filtered against a recently published candidate gene list. A total of 19 truncating variants and 17 missense variants were identified for genotyping in all prostate-affected and unaffected male participants. In all, 3 missense variants, PCTP, MCRS1, and ATRIP, demonstrated complete segregation and 1 missense variant, PARP2, demonstrated partial segregation with PC. In addition, 3 truncating variants, CYP3A43, DOK3, and PLEKHH3, demonstrated complete segregation and 3 truncation mutations, HEATR5B, GPR124, and HKR1, demonstrated partial segregation with PC. No segregating variants between the 3 families were shared. CONCLUSIONS: In all, 10 truncating or missense variants showed either complete or partial segregation with PC in the relevant families. CYP3A43 and PARP2 variants have been shown to occur in other familial PCs and our findings add to the contribution that these variants potentially have in the risk and development of PC in BRCAX cases.
Original languageEnglish
Pages (from-to)120.e9–120.e16
Number of pages8
JournalUrologic Oncology: Seminars and Original Investigations
Volume34
Issue number3
DOIs
Publication statusPublished - Mar 2016

Keywords

  • prostate cancer
  • exome sequencing
  • gene variants

Cite this

Hunter, S. M., Rowley, S. M., Clouston, D., KCon Fab Investigators, Li, J., Lupat, R., ... Thorne, H. (2016). Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer. Urologic Oncology: Seminars and Original Investigations, 34(3), 120.e9–120.e16. https://doi.org/10.1016/j.urolonc.2015.10.009
Hunter, Sally M. ; Rowley, Simone M. ; Clouston, David ; KCon Fab Investigators ; Li, Jason ; Lupat, Richard ; Krishnananthan, Nishanth ; Risbridger, Gail ; Taylor, Renea ; Bolton, Damien ; Campbell, Ian G. ; Thorne, Heather. / Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer. In: Urologic Oncology: Seminars and Original Investigations. 2016 ; Vol. 34, No. 3. pp. 120.e9–120.e16.
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title = "Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer",
abstract = "OBJECTIVE: A family history of prostate cancer (PC) is a well-recognized high-risk factor for the development of clinically significant PC. To date, traditional linkage and association studies have identified only a limited number of genes and specific gene variants that account for only a small proportion of PC risk. To identify novel PC predisposition genes we performed whole-exome sequencing of PC-affected men from families with a significant history of PC. METHODS AND MATERIALS: Exome sequencing was performed on 5 PC-affected men from 3 families where there were multiple cases of PCs and where diagnostic testing returned a negative result for BRCA1 and BRCA2 mutations. Genotyping was performed for all potentially predisposing variants detected within each family on the affected and unaffected male participants. RESULTS: Essential splice site, missense, and stop-lost variants were filtered against a recently published candidate gene list. A total of 19 truncating variants and 17 missense variants were identified for genotyping in all prostate-affected and unaffected male participants. In all, 3 missense variants, PCTP, MCRS1, and ATRIP, demonstrated complete segregation and 1 missense variant, PARP2, demonstrated partial segregation with PC. In addition, 3 truncating variants, CYP3A43, DOK3, and PLEKHH3, demonstrated complete segregation and 3 truncation mutations, HEATR5B, GPR124, and HKR1, demonstrated partial segregation with PC. No segregating variants between the 3 families were shared. CONCLUSIONS: In all, 10 truncating or missense variants showed either complete or partial segregation with PC in the relevant families. CYP3A43 and PARP2 variants have been shown to occur in other familial PCs and our findings add to the contribution that these variants potentially have in the risk and development of PC in BRCAX cases.",
keywords = "prostate cancer, exome sequencing, gene variants",
author = "Hunter, {Sally M.} and Rowley, {Simone M.} and David Clouston and {KCon Fab Investigators} and Jason Li and Richard Lupat and Nishanth Krishnananthan and Gail Risbridger and Renea Taylor and Damien Bolton and Campbell, {Ian G.} and Heather Thorne",
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Hunter, SM, Rowley, SM, Clouston, D, KCon Fab Investigators, Li, J, Lupat, R, Krishnananthan, N, Risbridger, G, Taylor, R, Bolton, D, Campbell, IG & Thorne, H 2016, 'Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer', Urologic Oncology: Seminars and Original Investigations, vol. 34, no. 3, pp. 120.e9–120.e16. https://doi.org/10.1016/j.urolonc.2015.10.009

Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer. / Hunter, Sally M.; Rowley, Simone M.; Clouston, David; KCon Fab Investigators; Li, Jason; Lupat, Richard; Krishnananthan, Nishanth; Risbridger, Gail; Taylor, Renea; Bolton, Damien; Campbell, Ian G.; Thorne, Heather.

In: Urologic Oncology: Seminars and Original Investigations, Vol. 34, No. 3, 03.2016, p. 120.e9–120.e16.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer

AU - Hunter, Sally M.

AU - Rowley, Simone M.

AU - Clouston, David

AU - KCon Fab Investigators

AU - Li, Jason

AU - Lupat, Richard

AU - Krishnananthan, Nishanth

AU - Risbridger, Gail

AU - Taylor, Renea

AU - Bolton, Damien

AU - Campbell, Ian G.

AU - Thorne, Heather

PY - 2016/3

Y1 - 2016/3

N2 - OBJECTIVE: A family history of prostate cancer (PC) is a well-recognized high-risk factor for the development of clinically significant PC. To date, traditional linkage and association studies have identified only a limited number of genes and specific gene variants that account for only a small proportion of PC risk. To identify novel PC predisposition genes we performed whole-exome sequencing of PC-affected men from families with a significant history of PC. METHODS AND MATERIALS: Exome sequencing was performed on 5 PC-affected men from 3 families where there were multiple cases of PCs and where diagnostic testing returned a negative result for BRCA1 and BRCA2 mutations. Genotyping was performed for all potentially predisposing variants detected within each family on the affected and unaffected male participants. RESULTS: Essential splice site, missense, and stop-lost variants were filtered against a recently published candidate gene list. A total of 19 truncating variants and 17 missense variants were identified for genotyping in all prostate-affected and unaffected male participants. In all, 3 missense variants, PCTP, MCRS1, and ATRIP, demonstrated complete segregation and 1 missense variant, PARP2, demonstrated partial segregation with PC. In addition, 3 truncating variants, CYP3A43, DOK3, and PLEKHH3, demonstrated complete segregation and 3 truncation mutations, HEATR5B, GPR124, and HKR1, demonstrated partial segregation with PC. No segregating variants between the 3 families were shared. CONCLUSIONS: In all, 10 truncating or missense variants showed either complete or partial segregation with PC in the relevant families. CYP3A43 and PARP2 variants have been shown to occur in other familial PCs and our findings add to the contribution that these variants potentially have in the risk and development of PC in BRCAX cases.

AB - OBJECTIVE: A family history of prostate cancer (PC) is a well-recognized high-risk factor for the development of clinically significant PC. To date, traditional linkage and association studies have identified only a limited number of genes and specific gene variants that account for only a small proportion of PC risk. To identify novel PC predisposition genes we performed whole-exome sequencing of PC-affected men from families with a significant history of PC. METHODS AND MATERIALS: Exome sequencing was performed on 5 PC-affected men from 3 families where there were multiple cases of PCs and where diagnostic testing returned a negative result for BRCA1 and BRCA2 mutations. Genotyping was performed for all potentially predisposing variants detected within each family on the affected and unaffected male participants. RESULTS: Essential splice site, missense, and stop-lost variants were filtered against a recently published candidate gene list. A total of 19 truncating variants and 17 missense variants were identified for genotyping in all prostate-affected and unaffected male participants. In all, 3 missense variants, PCTP, MCRS1, and ATRIP, demonstrated complete segregation and 1 missense variant, PARP2, demonstrated partial segregation with PC. In addition, 3 truncating variants, CYP3A43, DOK3, and PLEKHH3, demonstrated complete segregation and 3 truncation mutations, HEATR5B, GPR124, and HKR1, demonstrated partial segregation with PC. No segregating variants between the 3 families were shared. CONCLUSIONS: In all, 10 truncating or missense variants showed either complete or partial segregation with PC in the relevant families. CYP3A43 and PARP2 variants have been shown to occur in other familial PCs and our findings add to the contribution that these variants potentially have in the risk and development of PC in BRCAX cases.

KW - prostate cancer

KW - exome sequencing

KW - gene variants

UR - http://www.ncbi.nlm.nih.gov/pubmed/26585945

U2 - 10.1016/j.urolonc.2015.10.009

DO - 10.1016/j.urolonc.2015.10.009

M3 - Article

VL - 34

SP - 120.e9–120.e16

JO - Urologic Oncology: Seminars and Original Investigations

JF - Urologic Oncology: Seminars and Original Investigations

SN - 1078-1439

IS - 3

ER -