Hereditary Breast-Ovarian Cancer Syndrome in Russia

Sokolenko, Anna P.; Iyevleva, Aglaya G.; Mitiushkina, Natalia V.; Suspitsin, Evgeny N.; Preobrazhenskaya, Elena V.; Kuligina, E.; Voskresenskiy, Dmitry A.; Lobeiko, Oksana S; Krylova, Nadezhda Yu; Gorodnova, Tatiana V.; Buslov, Konstantin G.; Bit-Sava, E.M.; Dolmatov, Georgy D; Porhanova, N V; Polyakov, I. S.; Abysheva, Svetlana N.; Катанугина, А С; Baholdin, Dmitry V; Yanus, G.A.; Togo, Alexandr V.; Moiseyenko, Vladimir; Семиглазов, Владимир; Imyanitov, Evgeny N.

doi:10.32607/20758251-2010-2-4-31-35

Cited by 9 publications

(4 citation statements)

References 32 publications

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“…We tested multiple-gene panels for the presence of HBOCS predisposition markers in Tatar patients and detected several germline nucleotide variants in the BRCA1, BRCA2, CDK12, CDH1, CHEK2, FANCI, MUTYH, MSH2, and RAD51C genes, including some pathogenic variants previously reported in other populations. Strikingly, their prevalence and spectrum in Tatar HBOCS patients was found to be different to that reported in European populations, particularly in Russia ( 2 , 6 , 32 ).…”

Section: Discussioncontrasting

confidence: 86%

“…Ovarian (OC) and breast (BC) cancers are the leading causes of oncological mortality in women worldwide ( 1 ). Both cancers are highly heterogeneous with a strong hereditary component, as ~10–15% of OC and 5–7% of BC cases are hereditary ( 2 ). The hereditary predisposition for these cancers (hereditary breast and ovarian cancer syndrome, HBOCS) is caused by germline mutations in several genes, primarily those linked to DNA damage recognition and repair.…”

Section: Introductionmentioning

confidence: 99%

“…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 – 7 ), recent data indicates that many of them are absent in patients from the Tatar ethnic origin ( 8 ). Therefore, there is a clear clinical demand for identification of novel HBOCS predisposing nucleotide variants specific for the Tatar population.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2018

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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.

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Section: Discussioncontrasting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2018

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“…This lack of consistency might be explained by the interpopulation and inter-ethnic differences and result from the unique ethnic-specific genetic traits within the study cohorts (23). It is apparent now that the epidemiology and distribution of pathogenic germline mutations in BC are population-specific (24,25). Thus, the population-and ethnic background of the patient should be considered at the stage of the cancer risk genetic evaluation (23,26), as genetic risks might be mis-estimated if based on a data obtained in a study population with different ancestral (and, thus, genetic) background.…”

Section: Resultsmentioning

confidence: 99%

Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants

et al. 2020

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Genome instability-the increased tendency of acquiring mutations in the genome and ability of a cell to tolerate high mutation burden-is one of the drivers of cancer. Genome instability results from many causes including defects in DNA repair systems. Previously, it has been shown that germline pathogenic mutations in DNA Mismatch Repair (MMR) pathway cause cancer-predisposing Lynch Syndrome. We proposed that Lynch Syndrome-related germline mutations (LS-mutations) are associated with breast cancer (BC). In this study, we performed Targeted Next-Generation Sequencing of MMR pathway genes MLH1, MSH2, MSH6, EPCAM, and PMS2 in a cohort of 711 patients with hereditary BC, 60 patients with sporadic BC, and 492 healthy donors. Sixty-nine patients (9.7%) with hereditary BC harbored at least one germline mutation in the MMR pathway genes, of them 32 patients (4.5%) harbored mutations in MMR pathway genes which we define as pathogenic or likely pathogenic, and of them 26 patients (3.6%) did not have any pathogenic mutations in DDR pathway genes, compared to two mutations in MMR pathway genes (0.4%) detected in a group of 492 healthy donors [p = 0.00013, OR = 8.9 (CI 95% 2.2-78.4)]. Our study demonstrates that LS-mutations are present in patients with hereditary BC more frequently than in healthy donors, and that there is an association of hereditary BC and mutations c.1321G>A in MLH1, c.260C>G and c.2178G>C in MSH2, c.3217C>T in MSH6, c.1268C>G and c.86G>C in PMS2 genes. This finding provides a rationale for including pathogenic LS-mutations into genetic counseling tests for patients with hereditary BC.

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