Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.
Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.
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DOI：
10.1056/nejmoa1603144
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发表时间：
2016-08-04
期刊：
影响因子：
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通讯作者：
Nelson PS
中科院分区：
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作者：
Pritchard 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 ME;AlDubayan S;Han GC;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
dna修复基因（如BRCA2）的遗传突变与致命性前列腺癌的风险增加有关。虽然dna修复基因种系突变在非家族易感性的局限性前列腺癌患者中的流行率不足以保证常规检测，但这种突变在转移性前列腺癌患者中的频率尚未确定。我们招募了692名患有转移性前列腺癌的男性，他们没有被选择癌症家族史或诊断年龄。我们分离种系DNA，并使用多重测序法评估与常染色体显性癌症易感性综合征相关的20个DNA修复基因的突变。在82名男性（11.8%）中共鉴定出84种生殖系dna修复基因突变，这些突变被认为是有害的；16个基因发生突变，包括BRCA2（37例男性[5.3%]）、ATM（11例[1.6%]）、CHEK2（10例[534例有资料男性中的1.9%]）、BRCA1（6例[0.9%]）、RAD51D（3例[0.4%]）和PALB2（3例[0.4%]）。突变频率不因是否有前列腺癌家族史或诊断时的年龄而异。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名局限性前列腺癌男性的4.6% (P<0.001)，其中包括高风险男性，外显子组聚集联盟的患病率为2.7%，其中包括53,105名没有已知癌症诊断的人（P<0.001）。在我们的多中心研究中，转移性前列腺癌男性中介导dna修复过程的基因的种系突变发生率为11.8%，明显高于局限性前列腺癌男性的发生率。在患有转移性疾病的男性中，dna修复基因的种系突变频率根据诊断年龄或前列腺癌家族史没有显着差异。（由Stand Up To Cancer等机构资助。）
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. 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.)