Abstract
The Russian population consists of more than 100 ethnic groups, presenting a unique opportunity for the identification of hereditary pathogenic mutations. To gain insight into the landscape of heredity pathogenic variants, we employed targeted next-generation sequencing to analyze the germline mutation load in the DNA damage response and repair genes of hereditary breast and ovary cancer syndrome (HBOCS) patients of Tatar ethnicity, which represents ~4% of the total Russian population. Several pathogenic mutations were identified in DNA double-strand break repair genes, and the spectrum of these markers in Tatar patients varied from that previously reported for patients of Slavic ancestry. The CDK12 gene encodes cyclin-dependent kinase 12, the key transcriptional regulator of the genes involved in DNA damage response and repair. CDK12 analysis in a cohort of HBOCS patients of Tatar decent identified a c.1047-2A>G nucleotide variant in the CDK12 gene in 8 of the 106 cases (7.6%). The c.1047-2A>G nucleotide variant was identified in 1 of the 93 (1.1%) HBOCS patients with mixed or unknown ethnicity and in 1 of the 238 (0.42%) healthy control patients of mixed ethnicity (Tatars and non-Tatars) (p = 0.0066, OR = 11.18, CI 95% = 1.53–492.95, Tatar and non-Tatar patients vs. healthy controls). In a group of mixed ethnicity patients from Tatarstan, with sporadic breast and/or ovarian cancer, this nucleotide variant was detected in 2 out of 93 (2.2%) cases. In a cohort of participants of Slavic descent from Moscow, comprising of 95 HBOCS patients, 80 patients with sporadic breast and/or ovarian cancer, and 372 healthy controls, this nucleotide variant was absent. Our study demonstrates a strong predisposition for the CDK12 c.1047-2A>G nucleotide variant in HBOCS in patients of Tatar ethnicity and identifies CDK12 as a novel gene involved in HBOCS susceptibility.
Highlights
Ovarian (OC) and breast (BC) cancers are the leading causes of oncological mortality in women worldwide [1]
In Russia, most genetic risk assessment tests for hereditary breast and ovary cancer syndrome (HBOCS) include a panel of pathogenic nucleotide variants that are common among patients of European descent such as 5382insC, C61G, 185delAG, 4154delA, and 2080delA variants in the BRCA1 gene
In a cohort of participants from the Volga District, Republic of Tatarstan, the frequency of c.1047-2A>G mutation was significantly higher in HBOCS patients compared to healthy controls (9/199 vs. 1/238, p = 0.0066, OR = 11.18, CI 95% = 1.53–492.95, Table 4)
Summary
Ovarian (OC) and breast (BC) cancers are the leading causes of oncological mortality in women worldwide [1]. In Russia, most genetic risk assessment tests for HBOCS include a panel of pathogenic nucleotide variants that are common among patients of European descent such as 5382insC, C61G, 185delAG, 4154delA, and 2080delA variants in the BRCA1 gene. While those nucleotide variants have been comprehensively characterized in Russian Slavic populations [2, 5,6,7], recent data indicates that many of them are absent in patients from the Tatar ethnic origin [8]. There is a clear clinical demand for identification of novel HBOCS predisposing nucleotide variants specific for the Tatar population
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