Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing
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DOI：
10.1073/pnas.1115052108
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发表时间：
2011-11-01
影响因子：
11.1
通讯作者：
Swisher, Elizabeth M.
中科院分区：
文献类型：
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作者：
Walsh, Tom;Casadei, Silvia;Swisher, Elizabeth M.
BRCA1和BRCA2以及其他肿瘤抑制基因的遗传性功能丧失突变易患卵巢癌，但由于遗传性突变导致的疾病总体负担尚不清楚。利用靶向捕获和大规模平行基因组测序，我们筛选了原发性卵巢癌、腹膜癌或输卵管癌妇女基因组DNA中21个肿瘤抑制基因的种系突变。受试者在诊断时连续入组，未根据年龄或家族史进行选择。检测到所有类型的突变，包括点突变和大基因组缺失和插入。在360名受试者中，24%携带生殖系功能丧失突变：18%在BRCA 1或BRCA 2中，6%在BARD 1、BRIP 1、CHEK 2、MRE 11 A、MSH 6、NBN、PALB 2、RAD 50、RAD 51 C或TP 53中。这些基因中有6个以前没有涉及遗传性卵巢癌。原发癌的特征通常是突变基因的正常等位基因的基因组丢失。在有遗传性突变的女性中，>30%没有乳腺癌或卵巢癌家族史，>35%在诊断时为60岁或以上。更多的卵巢癌患者携带癌症易感突变，并且比以前认识到的更多基因。对所有患有卵巢癌、腹膜癌或输卵管癌的妇女，无论年龄或家族史如何，都需要进行遗传性癌症的全面基因检测。目前，临床基因检测是一个基因一个基因地进行的，每次检测都要花费数千美元。相比之下，大规模平行测序允许以低成本同时对许多基因进行这样的测试。
Inherited loss-of-function mutations in BRCA1 and BRCA2 and other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due to inherited mutations is not known. Using targeted capture and massively parallel genomic sequencing, we screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma. Subjects were consecutively enrolled at diagnosis and not selected for age or family history. All classes of mutations, including point mutations and large genomic deletions and insertions, were detected. Of 360 subjects, 24% carried germ-line loss-of-function mutations: 18% in BRCA1 or BRCA2 and 6% in BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53. Six of these genes were not previously implicated in inherited ovarian carcinoma. Primary carcinomas were generally characterized by genomic loss of normal alleles of the mutant genes. Of women with inherited mutations, >30% had no family history of breast or ovarian carcinoma, and >35% were 60 y or older at diagnosis. More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost.