转移性前列腺癌男性患者的遗传性DNA修复基因突变
Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.
作者信息
Pritchard Colin C, Mateo Joaquin, Walsh Michael F, De Sarkar Navonil, Abida Wassim, Beltran Himisha, Garofalo Andrea, Gulati Roman, Carreira Suzanne, Eeles Rosalind, Elemento Olivier, Rubin Mark A, Robinson Dan, Lonigro Robert, Hussain Maha, Chinnaiyan Arul, Vinson Jake, Filipenko Julie, Garraway Levi, Taplin Mary-Ellen, AlDubayan Saud, Han G Celine, Beightol Mallory, Morrissey Colm, Nghiem Belinda, Cheng Heather H, Montgomery Bruce, Walsh Tom, Casadei Silvia, Berger Michael, Zhang Liying, Zehir Ahmet, Vijai Joseph, Scher Howard I, Sawyers Charles, Schultz Nikolaus, Kantoff Philip W, Solit David, Robson Mark, Van Allen Eliezer M, Offit Kenneth, de Bono Johann, Nelson Peter S
机构信息
From 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.).
出版信息
N Engl J Med. 2016 Aug 4;375(5):443-53. doi: 10.1056/NEJMoa1603144. Epub 2016 Jul 6.
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.).
背景
DNA修复基因（如BRCA2）的遗传性突变与致命性前列腺癌风险增加相关。虽然在未因家族易感性而被挑选的局限性前列腺癌男性中，DNA修复基因种系突变的患病率不足以支持进行常规检测，但转移性前列腺癌患者中此类突变的频率尚未明确。
方法
我们招募了692例有记录的转移性前列腺癌男性，这些患者未因癌症家族史或诊断时的年龄而被挑选。我们分离种系DNA，并使用多重测序分析来评估与常染色体显性癌症易感性综合征相关的20个DNA修复基因中的突变。
结果
在82名男性（11.8%）中总共鉴定出84个推测为有害的种系DNA修复基因突变；在16个基因中发现了突变，包括BRCA2（37名男性[5.3%]）、ATM（11名[1.6%]）、CHEK2（10名[534名有数据的男性中的1.9%]）、BRCA1（6名[0.9%]）、RAD51D（3名[0.4%]）和PALB2（3名[0.4%]）。突变频率根据是否存在前列腺癌家族史或诊断时的年龄而无差异。总体而言，转移性前列腺癌男性中DNA修复基因种系突变的频率显著超过499例局限性前列腺癌男性（包括高危疾病男性）中4.6%的患病率（P<0.001），以及外显子聚合联盟中2.7%的患病率，该联盟包括53105名无已知癌症诊断的人（P<0.001）。
结论
在我们的多中心研究中，转移性前列腺癌男性中介导DNA修复过程的基因种系突变发生率为11.8%，显著高于局限性前列腺癌男性中的发生率。转移性疾病男性中DNA修复基因种系突变的频率根据诊断时的年龄或前列腺癌家族史无显著差异。（由“勇敢对抗癌症”等资助。）
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