The Ethnic-Specific Spectrum of Germline Nucleotide Variants in DNA Damage Response and Repair Genes in Hereditary Breast and Ovarian Cancer Patients of Tatar Descent

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.

A Splice Site Variant of CDK12 and Breast Cancer in Three Eurasian Populations

“…The results of our meta-analysis for the three studies in Tatars, Bashkirs and Kazakhs did not indicate an enrichment of carriers in cases and excluded a 2-fold increase in risk of breast cancer. When we include the hypothesis-generating study of Brovkina et al (6) into the meta-analysis, the combined OR 1.37 (95% CI 0.70; 2.69) still does not confirm a role as susceptibility factor and indicates that any risk conferred by the CDK12 variant is very unlikely to be higher than 3-fold.…”

“…While truncating CDK12 germline variants are very rare, the CDK12 c.1047-2A>G splice variant has recently been reported to occur quite commonly in Tatars where it has been found in some 5% of breast cancer patients and was associated with an about 10-fold increased breast cancer risk (6). This variant, rs138292741, has been recorded in the ExAc database with minor allele frequencies of 0.001 in South Asians and 0.0005 in Europeans, indicating that the Tatar population may harbor a founder effect and therefore might be particularly well suited for association studies regarding this CDK12 variant.…”

“…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 specifically 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.…”

Summary of BARD1 Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations

“…A total of 265 studies were further assessed by the full-text review, of which 145 studies not meeting the criteria (described in the Methods section and Figure S1 ) were excluded. Finally, for the analysis, we included 123 studies: 120 studies from the PubMed search and 3 hand-searched studies [ 15 , 16 , 18 , 19 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , …”

Human-likeness of antibody biologics determined by back-translation and comparison with large antibody variable gene repertoires

“…[5][6][7][8][9][10] Germline genes also may vary in individuals and ethnic subgroups, potentially biasing the maturation process in ways that may be of clinical relevance. 11 The increasing availability of large immunome datasets 4,[12][13][14][15] was leveraged to create a positionand gene-specific scoring matrix (PGSSM) for datasets in order to describe the human Ab sequence space. For this study we used the sequencing dataset from the Soto et al 4 dataset composed of the antibody sequencing from the blood compartment of three healthy human donors.…”