Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer
Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer
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DOI：
10.1086/318787
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发表时间：
2001-03-01
影响因子：
9.8
通讯作者：
Narod, SA
中科院分区：
文献类型：
--
作者：
Risch, HA;McLaughlin, JR;Narod, SA
在1995-96年期间，对加拿大安大略649例确诊为卵巢癌的偶发病例进行了BRCA 1和BRCA 2生殖系突变筛查。我们专门测试了这两个基因中最常见的11种突变。然后，对BRCA 1的外显子11进行蛋白质截短试验（PTT），对BRCA 1的其余部分进行变性梯度凝胶电泳，对BRCA 2的外显子10和11进行PTT。在所有134名患有交界性组织学肿瘤的妇女中未发现突变。在515名患有浸润性癌症的女性中，我们发现了60种突变，其中39种在BRCA 1中，21种在BRCA 2中。浸润性癌症女性的总突变频率为11.7%（95%置信区间[95%CI] 9.2%-14.8%），高于先前的估计。在60岁时诊断出的遗传性卵巢癌是由于BRCA 2。在报告一级亲属患有乳腺癌或卵巢癌的女性中，有19%的人发现了突变，而在没有一级亲属受影响的女性中，有6.5%的人发现了突变。与非携带者的亲属相比，携带BRCA 1突变病例的一级亲属患卵巢癌、乳腺癌、胃癌和白血病/淋巴瘤的风险分别增加了9倍、5倍、6倍和3倍，携带BRCA 2突变病例的亲属患结直肠癌的风险增加了3倍。对于BRCA 1突变的携带者，估计到80岁时卵巢癌的发病率为36%，乳腺癌为68%。在一级亲属的乳腺癌风险中，根据BRCA 1编码序列沿着的突变位置，存在一个强烈的趋势，几乎没有证据表明5'5分之一处突变的风险增加，但3' 5分之一处突变的风险增加8.8倍（95%CI 3.6-22.0），对应于基本上100%的携带者突变率。卵巢癌、结直肠癌、胃癌、胰腺癌和前列腺癌发生在BRCA 2突变携带者的一级亲属中，仅当突变位于外显子11的卵巢癌簇集区（OCCR）时，而当突变位于OCCR之外时，乳腺癌发生率较高。对于所有部位的癌症，BRCA 2突变的估计发生率男性高于女性，分别为53%和38%。过去的研究可能低估了BRCA 2对卵巢癌的贡献，因为该基因的突变主要导致迟发性癌症，而以前的工作更多地关注早发性疾病。如果在未来的研究中得到证实，根据BRCA 1编码序列沿着的突变位置，乳腺癌的转移趋势可能对BRCA 1突变携带者的治疗决策产生重大影响。同样，BRCA 2突变可能被证明是男性携带者患癌症的更大原因，而不是以前认为的。
A population-based series of 649 unselected incident cases of ovarian cancer diagnosed in Ontario, Canada, during 1995-96 was screened for germline mutations in BRCA1 and BRCA2. We specifically tested for 11 of the most commonly reported mutations in the two genes. Then, cases were assessed with the protein-truncation test (PTT) for exon 11 of BRCA1, with denaturing gradient gel electrophoresis for the remainder of BRCA1, and with PTT for exons 10 and 11 of BRCA2. No mutations were found in all 134 women with tumors of borderline histology. Among the 515 women with invasive cancers, we identified 60 mutations, 39 in BRCA1 and 21 in BRCA2. The total mutation frequency among women with invasive cancers, 11.7% (95% confidence interval [95% CI] 9.2%-14.8%), is higher than previous estimates. Hereditary ovarian cancers diagnosed at age 60 years were due to BRCA2. Mutations were found in 19% of women reporting first-degree relatives with breast or ovarian cancer and in 6.5% of women with no affected first-degree relatives. Risks of ovarian, breast, and stomach cancers and leukemias/ lymphomas were increased nine-, five-, six- and threefold, respectively, among first-degree relatives of cases carrying BRCA1 mutations, compared with relatives of noncarriers, and risk of colorectal cancer was increased threefold for relatives of cases carrying BRCA2 mutations. For carriers of BRCA1 mutations, the estimated penetrance by age 80 years was 36% for ovarian cancer and 68% for breast cancer. In breast-cancer risk for first-degree relatives, there was a strong trend according to mutation location along the coding sequence of BRCA1, with little evidence of increased risk for mutations in the 5' fifth, but 8.8-fold increased risk for mutations in the 3' fifth (95% CI 3.6-22.0), corresponding to a carrier penetrance of essentially 100%. Ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer-cluster region (OCCR) of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. Past studies may have underestimated the contribution of BRCA2 to ovarian cancer, because mutations in this gene cause predominantly late-onset cancer, and previous work has focused more on early-onset disease. If confirmed in future studies, the trend in breast-cancer penetrance, according to mutation location along the BRCA1 coding sequence, may have significant impact on treatment decisions for carriers of BRCA1-mutations. As well, BRCA2 mutations may prove to be a greater cause of cancer in male carriers than previously has been thought.