Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population
Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population
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DOI：
10.1093/hmg/ddi052
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发表时间：
2005-02-15
影响因子：
3.5
通讯作者：
King, MC
中科院分区：
文献类型：
--
作者：
Shaag, A;Walsh, T;King, MC
可以整合功能和基因组方法来有效筛选创始人群体中的致病等位基因。我们应用这种方法来分析德系犹太人中与癌症相关的细胞周期调节因子 CHEK2。我们首先在 CHEK2 上鉴定了两个扩展单倍型，它们与高风险家庭中的乳腺癌共分离。我们对代表每个单倍型的案例中的 CHEK2 进行了测序，发现了两个新的氨基酸取代，即激酶结构域中的 CHEK2.S428F 和 N 端区域中的 CHEK2.P85L。为了检测这些等位基因 CHEK2 功能的丧失，我们测试了它们在酿酒酵母中补充 Rad53 缺失的能力。 CHEK2.S428F无法补充Rad53，因此很大程度上废除了正常的CHEK2功能，而CHEK2.P85L补充了Rad53以及野生型CHEK2。流行病学分析与功能测试一致。在未选择家族史或诊断时年龄的女性乳腺癌患者中，CHEK2.S428F 杂合子的频率为 2.88% (47/1632)，在对照中为 1.37% (23/1673)（OR = 2.13,95% CI [1.26, 3.69]，P = 0.004），而 CHEK2.P85L 的频率为病例中为 0.92%，对照组为 0.83%。根据先证者的母亲、姐妹和女儿的经验，到 60 岁时，CHEK2.S428F 导致的乳腺癌风险估计为 0.17 (+/-0.08)。我们得出的结论是，CHEK2.S428F 使德系犹太女性患乳腺癌的风险增加两倍，而 CHEK2.P85L 是中性等位基因。总的来说，这些结果表明，选择具有与疾病共分离的扩展单倍型的先证者可以提高重测序工作的效率，并且酵母中的定量互补测试可用于评估具有高度保守功能的基因的变异。
Functional and genomic approaches can be integrated to screen efficiently for pathogenic alleles in founder populations. We applied such approaches to analysis of the cancer-associated cell cycle regulator CHEK2 in the Ashkenazi Jewish population. We first identified two extended haplotypes at CHEK2 that co-segregated with breast cancer in high-risk families. We sequenced CHEK2 in a case representing each haplotype and discovered two novel amino acid substitutions, CHEK2.S428F in the kinase domain and CHEK2.P85L in the N-terminal region. To assay these alleles for loss of CHEK2 function, we tested their capacity to complement Rad53 deletion in Saccharomyces cerevisiae. CHEK2.S428Ffailed to complement Rad53 and thus largely abrogates normal CHEK2 function, whereas CHEK2.P85L complemented Rad53 as well as did wild-type CHEK2. Epidemiologic analyses were concordant with the functional tests. Frequencies of CHEK2.S428F heterozygotes were 2.88% (47/1632) among female breast cancer patients not selected for family history or age at diagnosis and 1.37% (23/1673) among controls (OR = 2.13,95% CI [1.26, 3.69], P = 0.004), whereas frequencies of CHEK2.P85L were 0.92% among cases and 0.83% among controls. On the basis of the experience of mothers, sisters and daughters of probands, breast cancer risk due to CHEK2.S428F was estimated as 0.17 (+/-0.08) by age 60. We conclude that CHEK2.S428F increases breast cancer risk similar to2-fold among Ashkenazi Jewish women, whereas CHEK2.P85L is a neutral allelle. In general, these results suggest that selecting probands with extended haplotypes that co-segregate with disease can improve the efficiency of resequencing efforts and that quantitative complementation tests in yeast can be used to evaluate variants in genes with highly conserved function.