Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: A kin-cohort study in Ontario, Canada
Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: A kin-cohort study in Ontario, Canada
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DOI：
10.1093/jnci/djj465
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发表时间：
2006-12-06
影响因子：
10.3
通讯作者：
Narod, Steven A.
中科院分区：
文献类型：
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作者：
Risch, Harvey A.;McLaughlin, John R.;Narod, Steven A.
背景BRCA 1和BRCA 2突变在一般人群和各种类型的癌症中尚未得到很好的表征。我们调查了加拿大安大略新诊断的卵巢癌患者中这些突变的存在，并与其亲属中报告的癌症有关。研究方法：对1995年1月1日至1999年12月31日在加拿大安大略诊断为偶发卵巢癌的1171例NSCLC患者进行BRCA 1和BRCA 2基因的生殖系突变筛查。筛选包括检测常见变异，然后对长外显子进行蛋白质截短检测，然后分别对BRCA 1和BRCA 2的其余部分进行变性梯度凝胶电泳或变性高效液相色谱。考克斯回归分析被用来检查癌症的结果报告的情况下先证者为他们的8680个一级亲属。群体等位基因频率和相对危险度（RR）来自回归结果的SaundersBegg方法的扩展。特定的安大略癌症发病率被用来估计累积发病率的癌症到80岁的突变状态。结果如下：在977例浸润性卵巢癌患者中，75例有BRCA 1突变，54例有BRCA 2突变，总突变频率为13.2%（95%置信区间[CI] = 11.2%至15.5%）。在一般安大略人群中，携带BRCA 1基因突变的人患各种癌症的风险高于不携带者，包括卵巢癌（RR = 21，95% CI = 12 - 36）、女性乳腺癌（RR = 11，95% CI = 7.5 - 15）和睾丸癌（RR = 17，95% CI = 1.3 - 230）。携带BRCA 2突变的风险也高于不携带，尤其是卵巢癌。（RR = 7.0，95%CI = 3.1 ~ 16），女性和男性乳腺（RR = 4.6，95%CI = 2.7至7.8，RR 102，95%CI = 9.9至1050）和胰腺癌（RR 6.6，95%CI = 1.9至23）。癌症风险根据基因中突变的位置而不同。在携带BRCA 1突变的妇女中，估计80岁时的累积发病率为卵巢癌24%，乳腺癌90%，携带BRCA 2突变的妇女中卵巢癌8.4%，乳腺癌41%。对于一般安大略人群，BRCA 1和BRCA 2突变的估计携带者频率分别为0.32%（95%CI = 0.23%至0.45%）和0.69%（95%CI = 0.431%至1.10%）。结论：BRCA 1和BRCA 2突变在一般人群中可能比以前认为的更常见，并且可能与各种类型的癌症有关。
Background. BRCA1 and BRCA2 mutations in general populations and in various types of cancers have not been well characterized. We investigated the presence of these mutations in unselected patients with newly diagnosed incident ovarian cancer in Ontario, Canada, with respect to cancers reported among their relatives. Methods: A population series of 1171 unselected patients with incident ovarian cancer diagnosed between January 1, 1995, and December 31, 1999, in Ontario, Canada, was screened for germline mutations throughout the BRCA1 and BRCA2 genes. Screening involved testing for common variants, then protein truncation testing of long exons, and then denaturing gradient gel electrophoresis or denaturing high-performance liquid chromatography for the remainder of BRCA1 and BRCA2, respectively. Cox regression analysis was used to examine cancer outcomes reported by the case probands for their 8680 first-degree relatives. Population allele frequencies and relative risks (RRs) were derived from the regression results by an extension of SaundersBegg methods. Age-specific Ontario cancer incidence rates were used to estimate cumulative incidence of cancer to age 80 years by mutation status. Results: Among 977 patients with invasive ovarian cancer, 75 had BRCA1 mutations and 54 had BRCA2 mutations, for a total mutation frequency of 13.2% (95% confidence interval [CI] = 11.2% to 15.5%). Higher risks for various cancer types in the general Ontario population were associated with BRCA1 mutation carriage than with noncarriage, including ovarian (RR = 21, 95% CI = 12 to 36), female breast (RR = 11, 95% CI = 7.5 to 15), and testis (RR = 17, 95% CI = 1.3 to 230) cancers. Higher risks were also associated with BRCA2 mutation carriage than with noncarriage, particularly for ovarian (RR = 7.0,95% CI = 3.1 to 16), female and male breast (RR = 4.6, 95% CI = 2.7 to 7.8, and RR 102, 95% CI = 9.9 to 1050, respectively), and pancreatic (RR 6.6, 95% CI = 1.9 to 23) cancers. Cancer risks differed according to the mutation's position in the gene. Estimated cumulative incidence to age 80 years among women carrying BRCA1 mutations was 24% for ovarian cancer and 90% for breast cancer and among women carrying BRCA2 mutations was 8.4% for ovarian cancer and 41% for breast cancer. For the general Ontario population, estimated carrier frequencies of BRCA1 and BRCA2 mutations, respectively, were 0.32% (95% CI = 0.23% to 0.45%) and 0.69% (95% CI = 0.431% to 1.10%). Conclusions: BRCA1 and BRCA2 mutations may be more frequent in general populations than previously thought and may be associated with various types of cancers.