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Abstract
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.
Highlights
Familial risk of breast cancer is associated with high- to moderate-penetrance mutations in genes encoding DNA double-strand break sensors and repair proteins, such as BRCA1, BRCA2, PALB2, ATM, CHEK2, and others [1, 2]
CDK12 may have a interesting role as a new therapeutic target in oncology as its inhibition acts synthetically lethal with PARP1 inhibition, probably due to the role of CDK12 in homologous recombinational repair [21,22,23], but it seems to modulate the antitumor immune response [13]
It is important to clarify the role of CDK12 variants for breast cancer risk and treatment
Summary
Familial risk of breast cancer is associated with high- to moderate-penetrance mutations in genes encoding DNA double-strand break sensors and repair proteins, such as BRCA1, BRCA2, PALB2, ATM, CHEK2, and others [1, 2]. A recent report of Brovkina et al [6] has indicated a significant association of a c.1047-2A>G splice variant in the CDK12 gene that was found in 8 of 106 breast cancer cases (7.6%) from Tatarstan. Subsequent genotyping identified this mutation in 9/199 breast cancer patients (4.5%) from the Volga district of Tatarstan while it was present in just 1 of the 238 (0.4%) healthy control patients (p = 0.007), suggesting an about 10-fold increased risk for breast cancer. It is important to clarify the prevalence of germline CDK12 variants that may represent constitutive cancer susceptibility alleles
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