Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.

TitleInherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.
Publication TypeJournal Article
Year of Publication2016
AuthorsPritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, Carreira S, Eeles R, Elemento O, Rubin MA, Robinson D, Lonigro R, Hussain M, Chinnaiyan A, Vinson J, Filipenko J, Garraway L, Taplin M-E, AlDubayan S, G Han C, Beightol M, Morrissey C, Nghiem B, Cheng HH, Montgomery B, Walsh T, Casadei S, Berger M, Zhang L, Zehir A, Vijai J, Scher HI, Sawyers C, Schultz N, Kantoff PW, Solit D, Robson M, Van Allen EM, Offit K, de Bono J, Nelson PS
JournalN Engl J Med
Volume375
Issue5
Pagination443-53
Date Published2016 Aug 04
ISSN1533-4406
KeywordsAge Factors, Aged, Aged, 80 and over, DNA Mutational Analysis, DNA Repair, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Incidence, Male, Middle Aged, Neoplasm Metastasis, Prostatic Neoplasms
Abstract

BACKGROUND: Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established.

METHODS: We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes.

RESULTS: A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001).

CONCLUSIONS: In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. (Funded by Stand Up To Cancer and others.).

DOI10.1056/NEJMoa1603144
Alternate JournalN. Engl. J. Med.
PubMed ID27433846
PubMed Central IDPMC4986616
Grant ListP50 CA180995 / CA / NCI NIH HHS / United States
R01 CA193837 / CA / NCI NIH HHS / United States
P50 CA097186 / CA / NCI NIH HHS / United States
PC131820 / PC / NCI NIH HHS / United States
R01 CA175716 / CA / NCI NIH HHS / United States
K08 CA188615 / CA / NCI NIH HHS / United States
P50CA92629 / CA / NCI NIH HHS / United States
P50 CA092629 / CA / NCI NIH HHS / United States
P50CA097186 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA155169 / CA / NCI NIH HHS / United States
R35 CA197458 / CA / NCI NIH HHS / United States
1K08CA188615 / CA / NCI NIH HHS / United States
R01CA116337 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
P30CA008748 / CA / NCI NIH HHS / United States
R01 CA116337 / CA / NCI NIH HHS / United States
MR/M003272/1 / / Medical Research Council / United Kingdom
T32 GM007266 / GM / NIGMS NIH HHS / United States
PC140799 / PC / NCI NIH HHS / United States