GENETIC PREDICTORS OF TOXIC EFFECTS OF METHOTREXATE IN CANCER PATIENTS.

Today, methotrexate (MTX) is used in combination with other medicines to treat a wide range of malignancies. Despite its proven high efficacy, MTX often causes serious side effects, which may result in the need to reduce the dose of MTX or discontinue the drug altogether. This, in turn, can provoke the development of MTX resistance and cancer progression. Predicting the risk of MTX-induced toxicity is currently difficult due to the variability of pharmacokinetics and pharmacodynamics in different patients, so the scientific literature is intensively searching for potential biomarkers. Based on the data available in the current literature, we analyzed the relationship between variants in the genes encoding the key components of MTX intracellular metabolism and the MTX-induced side effects and drug response. According to the results of our work, the most studied variants are those of the SLC19A1 gene, which encodes the reduced folate carrier protein 1, and the MTHFR gene, which encodes the enzyme methylenetetrahydrofolate reductase. Studies of the effect of methylation of the promoter regions of genes on the therapeutic effect of MTX are also very promising. In conclusion, the study of molecular genetic markers of MTX toxicity is extremely relevant and necessary because it can help to avoid the effect of multidrug resistance and improve the quality of life and survival of patients.

CLINICAL SIGNIFICANCE OF BRCA1 GENE SEQUENCING AND ITS PROMOTER METHYLATION TESTING IN THE SEARCH STRATEGY FOR THERAPEUTIC TARGETS IN BREAST CANCER TREATMENT.

BACKGROUND: Currently, there is a great interest in the genetic testing of BRCA1 and BRCA2 due to the fact that for patients with breast cancer (BC) with pathogenic variants of these genes, the use of the PARP inhibitors could be also provided in addition to implemented treatment protocols. The aim of this study was to characterize the molecular genetic structure of the BRCA1 gene in BC patients without progenitor germline mutations taking into account the methylation state of the promoter region. MATERIALS AND METHODS: The study involved 210 patients with newly diagnosed BC. The most common germline pathogenic variants of the BRCA1 (185delAG, 5382insC, 4153delA, T300G) and BRCA2 (6174delT) genes were identified in the peripheral blood. A subgroup of 14 patients without progenitor pathological variants of the BRCA1 and BRCA2 genes and with a family history of cancer was randomly selected. For them, BRCA1 gene sequencing by Sanger and hypermethylation of the BRCA1 gene promoter region were analyzed. RESULTS: The following frequencies of BRCA1 mutations were determined in the general group: 5382insC - 8.6%, 4153delA - 0.5%, T300G - 0.5%. The analysis of the BRCA1 gene by Sanger sequencing revealed 11 BRCA1 gene variants in 10 out of 14 BC patients. All of them, according to the currently available data, were defined as "benign" and not clinically relevant. The frequency of the detection of hypermethylation of the BRCA1 gene promoter region in the randomly selected group of patients was 14.3%. CONCLUSIONS: In BC patients, not only common mutations but also the methylation status of the BRCA1 gene promoter region in the peripheral blood should be determined. The whole-genome sequencing of the BRCA1 gene may be the last step in determining the genetic characteristics of BC patients carried out to optimize the treatment and improve survival thanks to the higher prevalence of the progenitor mutations and hypermethylation of the BRCA1 gene promoter.