A protein-truncating mutation in CYP17A1 in three sisters with early-onset breast cancer
A protein-truncating mutation in CYP17A1 in three sisters with early-onset breast cancer
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DOI：
10.1002/humu.20237
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发表时间：
2005-10-01
期刊：
影响因子：
3.9
通讯作者：
Southey, MC
中科院分区：
文献类型：
--
作者：
Hopper, JL;Hayes, VM;Southey, MC
乳腺癌的激素病因是公认的。许多研究已经评估了类固醇激素代谢基因的多态性是否与乳腺癌风险相关。我们测量了CYP 17 A1 - 34 T> C（c.- 34 T> C）启动子多态性在一项基于人群的研究中，包括1，404名60岁以前诊断为乳腺癌的澳大利亚妇女（病例先证者），1，903名亲属和788名对照。家族内分析表明，CC基因型与平均风险的小幅增加有关。这一发现似乎受到三个早期发病的病例先证者的家庭的影响，这些先证者有多个受影响的姐妹篇。CYP 17 A1突变筛查发现一例先证者在38岁时诊断为生殖系蛋白截短突变（c.775C > T，p.Arg239X），导致酶无功能，并已报告在男性复合杂合子17 α-羟化酶缺乏症中。这种突变在34岁和42岁时被诊断患有乳腺癌的姐妹篇中携带，但在57岁未受影响的姐妹中没有携带。在其他受试病例先证者（48例有多个受影响亲属，241例随机选择）或对照组中均未发现。这项研究表明，类固醇激素代谢基因中可能存在罕见的突变，与显性遗传的乳腺癌高风险相关，并证明了如何使用基于人群的病例对照，家庭研究发现“高危易感基因”。
The hormonal etiology of breast cancer is well-established. Many studies have assessed whether polymorphisms in steroid hormone metabolism genes are associated with breast cancer risk. We measured the CYP17A1 -34T > C (c.-34T > C) promoter polymorphism in a population-based study of 1,404 Australian women with breast cancer diagnosed before age 60 years (case probands), 1,903 relatives, and 788 controls. Within-family analyses suggested the CC genotype was associated with, on average, a small increased risk. This finding appeared to be influenced by the families of three early,onset case probands with multiple affected sisters. CYP17A1 mutation screening revealed a case proband diagnosed at age 38 years who had a germline protein-truncating mutation (c.775C > T, p.Arg239X), which results in a nonfunctional enzyme and has been reported in a male compound heterozygote with 17 alpha-hydroxylase deficiency. This mutation was carried by both sisters diagnosed with breast cancer at ages 34 and 42 years, but not by a 57,year-old unaffected sister. It was not found in any of the other tested case probands (48 with multiple,affected relatives and 241 randomly selected) or controls. This study suggests there may be rare mutations in steroid hormone metabolism genes associated with a high dominantly-inherited breast cancer risk, and demonstrates how "high-risk susceptibility genes" might be discovered using population-based case-control,family studies.