A Splice Site Variant of CDK12 and Breast Cancer in Three Eurasian Populations
A Splice Site Variant of CDK12 and Breast Cancer in Three Eurasian Populations
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DOI：
10.3389/fonc.2019.00493
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发表时间：
2019-06-14
影响因子：
4.7
通讯作者：
Doerk, Thilo
中科院分区：
文献类型：
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作者：
Bogdanova, Natalia, V;Schuermann, Peter;Doerk, Thilo
CDK 12是细胞周期蛋白依赖性激酶家族的成员，其充当DNA损伤反应基因表达的调节剂。最近有报道称，CDK 12基因的c.1047-2A>G剪接位点变异与鞑靼族患者的遗传性乳腺癌和卵巢癌密切相关。为了更深入地了解c.1047-2A>G变异的潜在风险和人群传播，我们对鞑靼族、巴什基尔族和哈萨克族的三个乳腺癌病例对照系列进行了基因分型。我们在鞑靼人血统的6/155例病例和12/362例对照、巴什基尔人血统的0/96例病例和9/189例对照以及哈萨克人血统的1/131例病例和0/154例对照中确定了c.1047-2A>G（Mantel-Haenszel比值比0.72，95%CI 0.30-1.70，p = 0.45）。与不存在大效应一致，生物信息学分析预测c.1047-2A>G调节NAGNAG序列的选择性剪接，而不是构成功能丧失的等位基因，并且c.1047-2A>G杂合淋巴细胞的RT-PCR分析验证了预测的替代受体位点的使用。我们的研究证实了CDK 12 *c.1047-2A >G在鞑靼和巴什基尔人群中的高患病率，但排除了作为临床可操作的高风险乳腺癌突变的作用。
CDK12 is a member of the cyclin-dependent kinase family that acts as regulator of DNA damage response gene expression. A c.1047-2A>G splice site variant of the CDK12 gene was recently reported to strongly associate with hereditary breast and ovarian cancer in patients of Tatar ethnic origin. To gain more insight into the potential risk and the population spread of the c.1047-2A>G variant, we have genotyped three breast cancer case-control series of Tatar, Bashkir and Kazakh ethnicity. We identified c.1047-2A>G in 6/155 cases and 12/362 controls of Tatar ancestry, 0/96 cases and 9/189 controls of Bashkir ancestry, and 1/131 cases and 0/154 controls of Kazakh ancestry (Mantel-Haenszel odds ratio 0.72, 95% CI 0.30-1.70, p = 0.45). Consistent with the absence of a large effect, bioinformatic analyses predicted that c.1047-2A>G modulates alternative splicing of a NAGNAG sequence rather than constituting a loss-of-function allele, and RT-PCR analyses of c.1047-2A>G heterozygous lymphocytes verified the usage of the predicted alternative acceptor site. Our study confirms a high prevalence of CDK12*c.1047-2A >G in the Tatar and Bashkir population but excludes a role as a clinically actionable high-risk breast cancer mutation.