Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
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DOI：
10.1158/1078-0432.ccr-13-2287
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发表时间：
2014-02-01
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影响因子：
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通讯作者：
Swisher EM
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作者：
Pennington KP;Walsh T;Harrell MI;Lee MK;Pennil CC;Rendi MH;Thornton A;Norquist BM;Casadei S;Nord AS;Agnew KJ;Pritchard CC;Scroggins S;Garcia RL;King MC;Swisher EM
生殖系BRCA 1/2相关卵巢癌的特征包括化疗敏感性和生存率提高。体细胞BRCA 1/2突变和其他同源重组（HR）DNA修复基因突变的治疗影响尚不确定。使用靶向捕获和大规模平行基因组测序，我们评估了390例卵巢癌中30个基因的生殖系和体细胞功能丧失突变，包括BRCA 1，BRCA 2和HR途径中的11个其他基因。31%的卵巢癌在13个HR基因中的一个或多个中存在有害的生殖系（24%）和/或体细胞（9%）突变：BRCA 1，BRCA 2，ATM，BARD 1，BRIP 1，CHEK 1，CHEK 2，FAM 175 A，MRE 11 A，NBN，PALB 2，RAD 51 C和RAD 51 D。非浆液性卵巢癌的HR突变率与浆液性卵巢癌相似（28% vs. 31%，p=0.6），包括透明细胞癌、类卵巢癌和癌肉瘤。生殖系和体细胞HR突变的存在高度预测原发铂敏感性（p=0.0002）和改善的总生存期（p=0.0006），生殖系HR突变携带者的中位总生存期为66个月，体细胞HR突变病例为59个月，无HR突变病例为41个月。几乎三分之一的卵巢癌（包括浆液性和非浆液性组织学）中存在HR基因的生殖系或体细胞突变。体细胞BRCA 1/2突变和其他HR基因突变对总生存期和铂类药物反应性的积极影响与生殖细胞BRCA 1/2突变相似。非浆液性癌中HR突变的相似率支持将其纳入PARP抑制剂临床试验。
Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination (HR) DNA repair genes is uncertain. Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the HR pathway. 31% of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 HR genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Non-serous ovarian carcinomas had similar rates of HR mutations to serous carcinomas (28% vs. 31%, p=0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic HR mutations was highly predictive of primary platinum sensitivity (p=0.0002) and improved overall survival (p=0.0006), with median overall survival 66 months in germline HR mutation carriers, 59 months in cases with a somatic HR mutation, and 41 months for cases without an HR mutation. Germline or somatic mutations in HR genes are present in almost one-third of ovarian carcinomas, including both serous and non-serous histologies. Somatic BRCA1/2 mutations and mutations in other HR genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of HR mutations in non-serous carcinomas supports their inclusion in PARP inhibitor clinical trials.