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.
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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.
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).
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.).
N Engl J Med 2016; 375:443-453August 4, 2016DOI: 10.1056/NEJMoa1603144.
Pritchard CC1, Mateo J1, Walsh MF1, De Sarkar N1, Abida W1, Beltran H1, Garofalo A1, Gulati R1, Carreira S1, Eeles R1, Elemento O1, Rubin MA1, Robinson D1, Lonigro R1, Hussain M1, Chinnaiyan A1, Vinson J1, Filipenko J1, Garraway L1, Taplin ME1, AlDubayan S1, Han GC1, Beightol M1, Morrissey C1, Nghiem B1, Cheng HH1, Montgomery B1, Walsh T1, Casadei S1, Berger M1, Zhang L1, Zehir A1, Vijai J1, Scher HI1, Sawyers C1, Schultz N1, Kantoff PW1, Solit D1, Robson M1, Van Allen EM1, Offit K1, de Bono J1, Nelson PS1
- 1From the University of Washington (C.C.P., M. Beightol, C.M., B.N., H.H.C., B.M., T.W., S. Casadei, P.S.N.) and Fred Hutchinson Cancer Research Center (N.D.S., R.G., P.S.N.) - both in Seattle; the Institute of Cancer Research and Royal Marsden Hospital, London (J.M., S. Carreira, R.E., J.B.); Memorial Sloan Kettering Cancer Center (M.F.W., W.A., M. Berger, L.Z., A.Z., J. Vijai, H.I.S., C.S., N.S., P.W.K., D.S., M.R., K.O.), Weill Cornell Medical College (H.B., O.E., M.A.R.), and the Prostate Cancer Clinical Trials Consortium (J. Vinson, J.F.) - all in New York; the University of Michigan, Ann Arbor (D.R., R.L., M.H., A.C.); Howard Hughes Medical Institute, Chevy Chase, MD (A.C., C.S.); and Dana-Farber Cancer Institute, Boston (A.G., L.G., M.-E.T., S.A., G.C.H., E.M.V.A.).