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

被引：1269

作者：

Pritchard, C. C. ^{[1
]}

Mateo, J. ^{[3
,4
]}

Walsh, M. F. ^{[5
]}

De Sarkar, N. ^{[2
]}

Abida, W. ^{[5
]}

Beltran, H. ^{[6
]}

Garofalo, A. ^{[10
]}

Gulati, R. ^{[2
]}

Carreira, S. ^{[3
,4
]}

Eeles, R. ^{[3
,4
]}

Elemento, O. ^{[6
]}

Rubin, M. A. ^{[6
]}

Robinson, D. ^{[8
]}

Lonigro, R. ^{[8
]}

Hussain, M. ^{[8
]}

Chinnaiyan, A. ^{[8
,9
]}

Vinson, J. ^{[7
]}

Filipenko, J. ^{[7
]}

Garraway, L. ^{[10
]}

Taplin, M. -E. ^{[10
]}

AlDubayan, S. ^{[10
]}

Han, G. C. ^{[10
]}

Beightol, M. ^{[1
]}

Morrissey, C. ^{[1
]}

Nghiem, B. ^{[1
]}

Cheng, H. H. ^{[1
]}

Montgomery, B. ^{[1
]}

Walsh, T. ^{[1
]}

Casadei, S. ^{[1
]}

Berger, M. ^{[5
]}

Zhang, L. ^{[5
]}

Zehir, A. ^{[5
]}

Vijai, J. ^{[5
]}

Scher, H. I. ^{[5
]}

Sawyers, C. ^{[5
,9
]}

Schultz, N. ^{[5
]}

Kantoff, P. W. ^{[5
]}

Solit, D. ^{[5
]}

Robson, M. ^{[5
]}

Van Allen, E. M. ^{[10
]}

Offit, K. ^{[5
]}

de Bono, J. ^{[3
,4
]}

Nelson, P. S. ^{[1
,2
]}

机构：

[1] Univ Washington, Seattle, WA 98195 USA

[2] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA

[3] Inst Canc Res, London, England

[4] Royal Marsden Hosp, London, England

[5] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[6] Weill Cornell Med Coll, New York, NY USA

[7] Prostate Canc Clin Trials Consortium, New York, NY USA

[8] Univ Michigan, Ann Arbor, MI 48109 USA

[9] Howard Hughes Med Inst, Chevy Chase, MD USA

[10] Dana Farber Canc Inst, Boston, MA 02115 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2016年 / 375卷 / 05期

关键词：

OVARIAN-CANCER; BREAST; VARIANTS; BRCA1; RISK; ASSOCIATION; GENOMICS; CAPTURE; LYNCH;

D O I：

10.1056/NEJMoa1603144

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：443 / 453

页数：11

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