Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer
Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer
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DOI：
10.1001/jama.295.12.1379
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发表时间：
2006-03-22
影响因子：
120.7
通讯作者：
King, MC
中科院分区：
文献类型：
--
作者：
Walsh, T;Casadei, S;King, MC
背景BRCA 1和BRCA 2遗传突变的基因检测已经成为有严重乳腺癌或卵巢癌家族史的女性的护理不可或缺的一部分，但当他们实际携带致病性BRCA 1或BRCA 2突变时，未知数量的患者获得阴性（即野生型）结果。目的探讨乳腺癌易感基因BRCA 1、BRCA 2、CHEK 2、TP 53和PTEN在乳腺癌高危家系中未检出的突变频率和类型，为乳腺癌的诊断和治疗提供依据。BRCA 1和BRCA 2的（野生型）基因测试结果设计、设置和参与者在2002-2005年期间，来自300个美国家庭的先证者，有4例或更多乳腺癌或卵巢癌病例，但阴性BRCA 1和BRCA 2的（野生型）商业遗传检测结果通过多种基于DNA和RNA的基因检测方法进行筛选。方法检测BRCA 1和BRCA 2基因组重排以及CHEK 2、TP 53和PTEN所有类型的种系突变。主要结果测量先前未检测到的BRCA 1、BRCA 2、CHEK 2、TP 53、结果在300例先证者中，52例（17%）携带以前未发现的突变，其中35例（12%）携带BRCA 1或BRCA 2基因组重排，14例（5%）携带CHEK 2突变，3例（1%）携带TP 53突变。在BRCA 1和BRCA 2中，发现了22种不同的基因组重排，大小小于1 kb到大于170 kb;其中14种以前没有描述过，并且都是单独罕见的。在CHEK 2中，在2个捷克斯洛伐克血统的家族中发现了一个新的5.6 kb基因组缺失。在捷克和斯洛伐克共和国的631例乳腺癌患者中有8例（1.3%）发现了这种缺失，而在367例健康对照中没有发现这种缺失。对于所有重排，确定精确的基因组断点并验证诊断引物。3个TP 53突变家系除多例乳腺癌外，还包括儿童肉瘤或脑肿瘤。结论BRCA 1和BRCA 2的突变谱包括许多高频率、个别罕见的基因组重排。在BRCA 1和BRCA 2检测阴性（野生型）的乳腺癌和严重癌症家族史患者中，预计约12%的患者在这些基因中的一个中携带大的基因组缺失或重复，预计约5%的患者在CHEK 2或TP 53中携带突变。应向高危妇女提供鉴定这些突变的有效方法。
Context Genetic testing for inherited mutations in BRCA1 and BRCA2 has become integral to the care of women with a severe family history of breast or ovarian cancer, but an unknown number of patients receive negative (ie, wild-type) results when they actually carry a pathogenic BRCA1 or BRCA2 mutation. Furthermore, other breast cancer genes generally are not evaluated.Objective To determine the frequency and types of undetected cancer-predisposing mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN among patients with breast cancer from high-risk families with negative (wild-type) genetic test results for BRCA1 and BRCA2.Design, Setting, and Participants Between 2002-2005, probands from 300 US families with 4 or more cases of breast or ovarian cancer but with negative (wild-type) commercial genetic test results for BRCA1 and BRCA2 were screened by multiple DNA-based and RNA-based methods to detect genomic rearrangements in BRCA1 and BRCA2 and germline mutations of all classes in CHEK2, TP53, and PTEN.Main Outcome Measures Previously undetected germline mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN that predispose to breast cancer; frequencies of these mutations among families with negative genetic test results.Results Of the 300 probands, 52 (17%) carried previously undetected mutations, including 35 (12%) with genomic rearrangements of BRCA1 or BRCA2, 14 (5%) with CHEK2 mutations, and 3 (1%) with TP53 mutations. At BRCA1 and BRCA2, 22 different genomic rearrangements were found, of sizes less than 1 kb to greater than 170 kb; of these, 14 were not previously described and all were individually rare. At CHEK2, a novel 5.6-kb genomic deletion was discovered in 2 families of Czechoslovakian ancestry. This deletion was found in 8 of 631 (1.3%) patients with breast cancer and in none of 367 healthy controls in the Czech and Slovak Republics. For all rearrangements, exact genomic breakpoints were determined and diagnostic primers validated. The 3 families with TP53 mutations included cases of childhood sarcoma or brain tumors in addition to multiple cases of breast cancer.Conclusions The mutational spectra of BRCA1 and BRCA2 include many high-penetrance, individually rare genomic rearrangements. Among patients with breast cancer and severe family histories of cancer who test negative ( wild type) for BRCA1 and BRCA2, approximately 12% can be expected to carry a large genomic deletion or duplication in one of these genes, and approximately 5% can be expected to carry a mutation in CHEK2 or TP53. Effective methods for identifying these mutations should be made available to women at high risk.