Numerous studies indicate an extremely high rate of loss of heterozygosity on the short arm of chromosome 19, in the chromosomal segment 19p13.3, for different types of neoplasia: coion, cervical, breast cancers, myeloid leukemia. High rates of 19p13.3 loss of heterozygosity suggest that it contains one or more tumor suppressor genes. Our study of molecular pathology of the SEMA6B gene located in a critical area in breast cancer samples reveals features characteristic of the tumor suppressor gene. The frequency of abnormal methylation of the 5' region of the gene and the rate of loss of heterozygosity in breast cancer samples equal correspondingly 38% and 50%. A germinal mutation in an evolutionarily conserved region of the SEMA6B gene was detected in one of the breast cancer patients.

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Genome-Wide Methylotyping Resolves Breast Cancer Epigenetic Heterogeneity and Suggests Novel Therapeutic Perspectives

Epigenomics (2019)

А. С. Танас В.О. Сигин Alexey I. Kalinkin Н. В. Литвяков Е. М. Slonimskaya

Aim: To provide a breast cancer (BC) methylotype classification by genome-wide CpG islands bisulfite DNA sequencing. Materials & methods: XmaI-reduced representation bisulfite sequencing DNA methylation sequencing method was used to profile DNA methylation of 110 BC samples and 6 normal breast samples. Intrinsic DNA methylation BC subtypes were elicited by unsupervised hierarchical cluster analysis, and cluster-specific differentially methylated genes were identified. Results & conclusion: Overall, six distinct BC methylotypes were identified. BC cell lines constitute a separate group extremely highly methylated at the CpG islands. In turn, primary BC samples segregate into two major subtypes, highly and moderately methylated. Highly and moderately methylated superclusters, each incorporate three distinct epigenomic BC clusters with specific features, suggesting novel perspectives for personalized therapy.

Epigenomics

Methylated DNA immunoprecipitation

CpG site

Bisulfite sequencing

Illumina Methylation Assay

Differentially methylated regions

Bisulfite

10.2217/epi-2018-0213

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17P Cyclophosphamide influence on survival probability of breast cancer patients depending on leukotriene receptor LTB4R gene expression level

Annals of Oncology (2020)

Alexey I. Kalinkin В.О. Сигин А. С. Танас V. V. Strelnikov

Log-rank test

10.1016/j.annonc.2020.08.2176

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Design of Marker Panels for Prediction of Neoadjuvant Chemotherapy Response of Triple-Negative Breast Tumors Based on the Results of Genome-Wide DNA Methylation Screening

Russian Journal of Genetics (2022)

Alexey I. Kalinkin В.О. Сигин E. Ignatova М. А. Фролова Ekaterina Kuznetsova

Human genetics

10.1134/s1022795422070080

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Мутации криптических сайтов сплайсинга в некодирующих областях гена ABCA4 при болезни Штаргардта

Медицинская генетика (2016)

О. Карандашева В. Жоржоладзе Л. Шеремет B A Kuznetsova С. Танас

Background. Mutations in the ABCA4 gene cause Stargardt disease and other blinding autosomal recessive retinal disorders. However, sequencing of the complete coding sequence in patients with clinical features of Stargardt disease sometimes fails to detect both mutations required to cause the disease. It has previously been hypothesized that mutations near rare alternate splice junctions in ABCA4 might cause disease by increasing the probability of mis-splicing at these sites. Deep next-generation sequencing of RNA extracted from human donor eyes revealed 15 alternate exons that are weakly expressed in normal human retina. Cryptic intronic splice sites, activation of which by mutations might lead to the formation of ABCA4 disease causing alleles, have been identified. Objective. To analyze the cryptic splice sites in the noncoding regions of the ABCA4 gene in Russian patients with Stargardt disease. Material and methods. High throughput parallel semiconductor sequencing of all previously described minor exons was performed on peripheral blood cells DNA from 29 patients with Stargardt disease. Results. In the group of patients under study we have identified only genetic variants in the cryptic splice sites that represent common polymorphisms and that cannot thus be interpreted as disease causing mutations. Our cohort of the patients lacked apparently disease causing intronic nucleotide substitutions that were previously identified in the North American and European populations. Conclusion. Failure to identify ABCA4 intronic mutations in this study may be explained by low representation of patients with one or no exonic mutations in our cohort and does not compromise the utility of intron cryptic splice sites sequencing as a part of Stargardt disease molecular genetic diagnostics.

ABCA4

Stargardt disease

splice

Splice site mutation

10.1234/xxxx-xxxx-2016-6-31-36

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НОВЫЕ МАРКЁРЫ АНОМАЛЬНОГО МЕТИЛИРОВАНИЯ ДНК ПРИ ОСТРОМ МИЕЛОИДНОМ ЛЕЙКОЗЕ У ДЕТЕЙ, ИДЕНТИФИЦИРОВАННЫЕ НЕПРЕДВЗЯТЫМ СКРИНИНГОМ ДИФФЕРЕНЦИАЛЬНОГО МЕТИЛИРОВАНИЯ ГЕНОМОВ

Медицинская генетика (2015)

В. В. Руденко В. С. Немировченко А. С. Танас А. В. Попа Svetlana Kazakova

By use of the unbiased differential DNA methylation screening we have identified 16 novel genome loci aberrantly methylated in pediatric acute myeloid leukemia. Almost all of them belong to promoter CpG islands except one corresponding to the intergenic CpG island on the chromosome 7p21.1. Two of the genes shown to be abnormally methylated in our study encode proteins involved in the epigenetic regulation of gene expression, namely, RXRA, involved in the posttranslational hystone modifications, and KHSRP/KSRP, that binds to adenine/uracil rich RNA sequences and regulates posttranscriptional RNA stability. We suggest a system of 13 DNA methylation markers, corresponding to the promoter regions of the EGFLAM, RXRA, MAFA, TMEM176A/TMEM176B, KHSRP, TMEM200B, ABCG4, GSG1L, CLDN7, CXCL14, DLK2, AIFM3 and SOX8 genes, for the detection of minimal residual disease in pediatric acute myeloid leukemia.

CpG site

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CHANGES IN DNA METHYLATION PROFILE IN TAMOXIFEN-RESISTANT MCF-7 SUBLINES

Siberian Journal of Oncology (2019)

Olga E. Andreeva В.О. Сигин V. V. Strelnikov А. С. Танас Alexander M. Scherbakov

Abstract Introduction. We have previously shown the feasibility of hormonal resistance horizontal distribution from cell to cell, with the joint cultivation of sensitive and resistant cells and/or through exosomes secreted by resistant cells. What is the mechanism of such resistance distribution, and how do cells with secondary resistance reproduce the characteristics of donor resistant cells? To answer these questions, we analyzed the overall level of DNA methylation in MCF-7 estrogen-dependent breast cancer cells and estrogen-independent sublinia. The purpose of the study was to analyze DNA methylation profiles for the development of hormonal resistance by breast cancer cells and for resistant phenotype further accession. Methods. DNA methylation was evaluated by the RRBS (Reduced Representation Bisulfite Sequencing) method in MCF-7 breast cancer cells and their resistant sublines. Results. 19 CpG dinucleotides, differentially and generally unidirectionally methylated in cells with primary and secondary resistance to tamoxifen, were detected. Differential changes in methylation were found for DNA regions that regulated the expression of six protein-coding genes: PRKCZ, TRAPPC9, AS IC2, C2CD4A, ZNF787, CRTAC 1. Bioinformatics analysis showed that two of these six genes, PRKCZ (protein kinase C Zeta) and TRAPPC9 (Trafficking Protein Particle Complex Subunit 9) were directly involved in the regulation of NF-κB activity. Conclusion. The data obtained indicate the existence of common DNA patterns, the methylation of which varies in the same direction in cells with primary and secondary resistance. The involvement of two of the identified genes in the regulation of NF-κB may indicate the inclusion of the latter in the formation of a resistant phenotype of tumor cells, even under conditions of horizontal transfer of resistance.

MCF-7

CpG site

Bisulfite sequencing

10.21294/1814-4861-2019-18-5-45-53

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Результаты использования медицинской технологии определения микроделеции 22q11.2 методом микросателлитного анализа у больных c диагнозом вело-кардио-фациальный синдром / ДиДжорджи синдром

Медицинская генетика (2016)

Valeriya Nemtsova V. V. Strelnikov B A Kuznetsova В. В. Руденко Anna S. Kazakova

DiGeorge syndrome (OMIM 188400) and velo-cardio-facial syndrome (VCFS) (OMIM 192430) constitute a group of «CATCH 22», which is characterized by microdeletions of different lengths in the chromosome 22q11.2 region. Microdeletion rate is quite high, and is 1 in 4000 live births in the population, making this disease one of the most common microdeletion syndromes. At the present time to identify microdeletions along with standard high-resolution chromosome analysis methods, comparative genomic hybridization, FISH analysis, fragment analysis and multiplex ligation reaction are used. The advantages of microsatellite analysis are speed, efficiency and cheapness. We present the results of DNA diagnostics on 389 patients, referred to the laboratory with a diagnosis of CATCH 22, using the medical technology which is an effective method of rapid detection of deletions of chromosome 22 sequences by amplification of highly polymorphic microsatellite DNA loci. The diagnostic panel includes STR-markers mapped in a critical region of chromosome 22. Markers D22S264 , D22S1638 , D22S941 , D22S873 , D22S4 , D22S1709 are located in the smallest region of overlap of all deletions identified to date. Diagnosis is carried out on DNA obtained from peripheral blood lymphocytes of patients and their parents. DNA diagnostics is possible to confirm the diagnosis in the case of fetal death or premature death of the child on the formalin-fixed paraffin embedded autopsy material.

DiGeorge syndrome

Comparative genomic hybridization

Multiplex

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