Relevance: According to the International Agency for Research on Cancer (IARC), lung cancer (LC) currently ranks first in cancer incidence and mortality worldwide. The gold standard of LC diagnostics is the histological verification, the determination of the degree of invasion and tumor phenotype. At first glance, epigenetic methods seem to be secondary after determining the patient’s genetic profile. However, standard genetic analysis reveals only the DNA nucleotide sequence. Thus, epigenetic analysis is the only method that allows detecting potential abnormalities in cells. An important difference between genetic and epigenetic changes is that drugs are efficient against epigenetic changes but absolutely powerless against genetic mutations. The purpose of the study was to review and analyze the available molecular genetic methods for DNA methylation profiling in lung cancer. Results: All these observations support the hypothesis that methylation profiling in body fluids can help determine the people predisposed to or affected by LC. Circulating acellular DNA in the blood plasma contains tumor-specific mutations and disease-related DNA methylation patterns. Identifying new biomarkers-precursors of a potential cancer susceptibility or aggressiveness in such DNA would be a considerable advancement in prognostic medicine for patients at high risk of developing LC. Conclusion: A low level of LC detection might limit the number of DNA samples of patients with LC included in the studies. This is also the reason why specific methylation biomarkers have not yet been confirmed for clinical use. Future research on a larger number of blood samples, combined with the entire epigenome studies, may contribute to finding a group of LC biomarkers to improve LC detection.

-It is well known that somatic mutations are induced by ionizing irradiation. We have previously reported the measurement of mutant frequency (MF) on the T-cell receptor (TCR) gene in mouse T-lymphocytes after irradiation by flow cytomery. In this study, we developed an in vitro system using murine EL-4 lymphoma cells and observed frequency of cells defective in TCR gene expression after exposure to ionizing irradiation. EL-4 cells were stained with fluorescein-labeled anti-CD4 and phycoerythrin-labeled anti-CD3 antibodies. They were analyzed with a flow cytometer to detect mutant EL-4 cells lacking surface expression of TCR/CD3 complexes which showed CD3− , CD4 + due to a somatic mutation at the TCR genes. Mutant cells could be observed at 2 days after 3 Gy irradiation. MF of EL-4 cells was 6.7 × 10 −4 for 0 Gy and the value increased to the maximum level of 39 × 10 −4 between 4 and 8 days after 3 Gy irradiation and these data were found to be best fitted by a linear-quadratic doseresponse model. After the peak value the TCR MF gradually decreased with a half-life of approximately 3.2 days. We also examined the hprt mutant frequencies at seven days after irradiation and the cytokinesisblocked micronucleus frequency at 20 hrs after irradiation. The frequencies of hprt mutation and micronuclei were found to be best fitted by a linear-quadratic dose-response model and a linear dose-response model, respectively. The method to detect mutation on TCR gene is quick and easy in comparison with other methods and is considered useful for the mutagenicity test.

Background: Today, genomic changes are an important cause of the occurrence, growth and progression of cancer. Technological advances in cancer genomic analysis platforms have made it possible to identify genomic alterations that may influence response to lung cancer treatment. Methods: The study examined tumor growth-inhibiting oncogenes and genes responsible for cell growth and division to identify mutations characteristic of malignant lung tumors. The mutations were studied in 400 postoperative samples after amplifying p53 and HRAS fragments and p53, p21Waf1, MDM2 mRNA. p53 or p21Waf1 were expressed in 50% of squamous cell carcinomas and adenocarcinomas of the lung. Results:The study examined tumor growth-inhibiting oncogenes and genes responsible for cell growth and division to identify mutations characteristic of malignant lung tumors. The mutations were studied in 400 postoperative samples after amplifying p53 and HRAS fragments and p53, p21Waf1, MDM2 mRNA. p53 or p21Waf1 were expressed in 50% of squamous cell carcinomas and adenocarcinomas of the lung. HRAS mutations were present in most squamous cell carcinomas and adenocarcinomas of the lung. EcoR1-and Pst1-restriction enzymes destroyed the RT-PCR product of the p53 and p21Waf1 mRNA and increased the level of detected mutations in lung adenocarcinoma to 75% and 50 %, respectively. EGFR mutations were more frequent in lung adenocarcinoma than in lung squamous cell carcinoma. Mutations in EGFR exons 19 and 21 found in 65 of 263 lung tumor samples indicated the tumor sensitivity to EGFR tyrosine kinase inhibitors. EGFR deletions in exon 19 occurred mainly in adenocarcinoma, L858R mutations in EGFR exon 21 were quite common in lung adenocarcinoma. Conclusion: The mutations detected in most squamous cell carcinomas and adenocarcinomas of the lung could be used to diagnose and predict the disease severity and targeted therapy efficacy.

Relevance: According to the International Agency for Research on Cancer (IARС), breast cancer ranks 1st-2nd among other cancers globally [1], including Kazakhstan [2]. In Kazakhstan, the annual growth in breast cancer incidence exceeds 26.6%. In 2018-2019, breast cancer was the 3rd most common cause of cancer death in Kazakhstan, accounting for 8.7-8.1 percent, respectively. Early detection of breast cancer remains an acute issue. In particular, early detection should be improved. Epigenetic studies of cancer patients confirm that epigenetic biomarkers could be used as early cancer diagnostic markers, including breast cancer. The study aimed to find specific diagnostic markers by methylation profiling of peripheral blood mononuclear cell (PBMC) DNA in breast cancer patients. Results: Plasma samples of the Kazakhstani population with breast cancer possessed mononuclear cell methylation markers in CpG islets associated with JAM3, C17orf64, MSC, and C7orf51 genes and the CpG islet associated with the intergenic region on chromosome 5, chr5: 77,208,034-77,329,434, which were missing in healthy individuals. These biomarkers allow differentiating breast cancer from other cancers with a specificity of 0.91 and a sensitivity of 0.94 compared to methylation data from open DNA methylation databases (for Illumina 450K): TCGA, GSE40279, GSE61496, GSE76269 и GSE66836. Conclusion: Early breast cancer detection method using peripheral blood mononuclear cell DNA methylation profile, namely in CpG islets associated with JAM3, C17orf64, MSC, and C7orf51 genes and the CpG islet associated with the intergenic region on chromosome 5, chr5: 77,208,034-77,329,434 is enough specific and sensitive to use it in breast cancer screening.

Relevance: According to the International Agency for Research on Cancer (IARС), breast cancer ranks 1st-2nd among other cancers globally [1], including Kazakhstan [2]. In Kazakhstan, the annual growth in breast cancer incidence exceeds 26.6%. In 2018- 2019, breast cancer was the 3rd most common cause of cancer death in Kazakhstan, accounting for 8.7-8.1 per cent, respectively. Early detection of breast cancer remains an acute issue. In particular, early detection should be improved. Epigenetic studies of cancer patients confirm that epigenetic biomarkers could be used as early cancer diagnostic markers, including breast cancer. The purpose was to find specific diagnostic markers by methylation profiling of peripheral blood mononuclear fraction DNA in breast cancer patients. Results: Plasma samples of the Kazakhstani population with breast cancer possessed mononuclear fraction methylation markers in CpG islets associated with JAM3, C17orf64, MSC, and C7orf51 genes and the CpG islet associated with the intragenic region of the 5, chr5: 77,208,034-77,329,434 chromosome, which were missing in healthy individuals. These biomarkers allow differentiating breast cancer from other cancers with a specificity of 0.91 and a sensitivity of 0.94 compared to methylation data from open DNA methylation databases (for Illumina 450K): TCGA, GSE40279, GSE61496, GSE76269 и GSE66836. Conclusion: Early breast cancer detection method using peripheral blood mononuclear fraction DNA methylation profile, namely in CpG islets associated with JAM3, C17orf64, MSC, and C7orf51 genes and the CpG islet associated with the intragenic region of the 5, chr5: 77,208,034-77,329,434 chromosome is enough specific and sensitive to use it in breast cancer screening

Introduction. The growth of primary breast tumor morbidity in the last ten years and increased number of patients with disseminated breast cancer in the Republic of Kazakhstan require the search for methods of early diagnosis of malignant tumors. Determination of breast cancer markers in epigenetic studies allows to use them as diagnostic signs of the presence of malignant tumor and as predictors of treatment effectiveness in patients with this pathology.Aim. To perform  a search for therapeutic and prognostic breast cancer markers.Materials and methods. The study included samples of biological material (peripheral blood) of 50 deemed healthy individuals and 103 patients with locally advanced and disseminated breast cancer receiving special therapy. The following methods were used: blood collection, DNA extraction, creation of DNA methylation profiles, sequencing, statistical data analysis.Results. The results of search for epigenetic mutations in peripheral blood of patients with breast cancer showed their role as specific diagnostic, therapeutic and prognostic markers with specificity 0.91 % and sensitivity 0.94 %. The hypothesis on therapeutic  significance of identified earlier diagnostic markers in patients  with breast cancer, namely hypermethylation of CpG islands associated with genes JAM3, C17orf64,  MSC, C7orf51  and CpG island associated with intragene part of chromosome 5 (chr5: 77,208,034–77,329,434) was tested and confirmed.Conclusion. A correlation between DNA methylation characteristics and disease progression during treatment was shown. The study results can be used in clinical practice: epigenetic markers, such as methylation in the CpG islets associated with the JAM3, C17orf64, MSC, C7orf51 genes, and in the CpG islet associated with the intragenic site of chromosome 5 (chr5: 77,208,034–77,329,434) can be used as prognostic markers and therapeutic predictors of breast cancer.

Relevance: According to the International Agency for Research on Cancer (IARС), lung cancer (LC) today ranks first in cancer incidence worldwide [1]. In the Republic of Kazakhstan, about 3800 new cases of LC and more than 2000 deaths from LC are registered each year (one-year mortality exceeds 49.4%) [2]. This supports the relevance of early LC diagnostics. The study of DNA methylation in human peripheral blood mononuclear cells (PBMC) suggests its use as an early diagnostic and prognostic marker for LC before detecting a malignant neoplasm by visual diagnostic methods. The purpose of the study was to find specific diagnostic and prognostic markers by DNA methylation profiling of PBMC in patients with LC. Results: Methylation markers of blood mononuclear fraction were detected in CG islets associated with genes ICAM5, mir138, SYNE1, and KLK4 in 97% of plasma samples from patients with LC and were absent in healthy people. The usability of these markers to differentiate LC from 16 other cancers using NCBI GEO and TCGA methylation data was demonstrated with a specificity level of 0.96 and a sensitivity of 0.84. Conclusion: The specificity and sensitivity of the method of LC early diagnostics and prognosis based on the methylation of blood mononuclear cells (detection of methylation of CG islets associated with the ICAM5, mir138, SYNE1, and KLK4 genes in PBMC) are enough to use it in screening for LC.

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