Recently multiple data accumulated concerning mutations in the ESR1 gene coding estrogen receptor α (mutESR1) and in the LYN gene coding non receptor tyrosine kinase SRC family member (mutLYN) that are associated with endocrine therapy resistance and that could be considered as markers of endocrine therapy efficiency. In case of gynecologic cancers including ovarian cancer the most frequent mutESR1 are ESR1^L536H/P/R/V , ESR1^Y537S/N/C/H, ESR1^D538G that emerge in the course of hormonotherapy especially using aromatase inhibitors. mutLYN including LYN^E159K, LYN^D189Y, LYN^K209N, LYN^A370T, LYN^G418R, LYN^A503D are also identified. mutESR1 and mutLYN increase transcriptional activity of estrogen receptor α (ERα) coded with ESR1 gene and catalytic activity of LYN kinase inducing endocrine therapy resistance. Interdependence of ESR1 and LYN genes is revealed at the level of proteins that they code as the kinases of the SRC family including LYN activate ERα-dependent transcription due to the phosphorylation of ERα at Y537 amino-acid residue that is the most frequently mutated in tumors with endocrine therapy resistance.

 The aim of the review is revealing the clinical correlations of mutESR1 and mutLYN with the ovarian cancer endocrine therapy resistance that opens perspectives of mutESR1 and mutLYN use as new predictive markers of ovarian cancer and development of more efficient anti-tumor medicaments. In the review the information obtained from PubMed database for the last 20 years using the following key words: ESR1, LYN, mutation(s), estrogen receptor α (ERα), LYN kinase, SRC family kinases, ovarian cancer, gynecologic(al) cancer is discussed.

Introduction. Neurofibromatosis type 1 (NF1) is the most common hereditary tumor syndrome (frequency of its occurrence in the world is 1 : 3000 of the population). The main clinical manifestations of the disease are multiple café-au-lait macules on the skin and neurofibromas, skeletal abnormalities and cognitive deficits. The disease is based on mutations in the oncosuppressor gene NF1. This disease is characterized by significant clinical polymorphism of manifestations, even among members of the same family. No geno-phenotypic correlations were found for NF1. Therefore, it is assumed that modifier genes are the cause of the varying expressiveness of the disease.

 Materials and methods. Clinical-epidemiological and molecular-genetic research of patients with NF1 in the Republic of Bashkortostan (RB) was carried out. Sequencing was used to search for intragenic mutations in 57 exons of the NF1 gene. Microsatellite analysis was used to detect the deletion of the entire gene.

Results. The frequency of occurrence of NF1 in RB was 1 : 10153 of the population. Analysis of the clinical manifestations of NF1 in RB patients showed a lower incidence of brain cysts in patients born in mixed marriages, which indicates the protective role of mestization. In patients with NF1 who inherited the disease from the mother, a more frequent development of skeletal anomalies and facial dysmorphism was determined. We identified 1 deletion of the entire NF1 gene in 1 patient and 14 intragenic mutations (c.205-1G>C, с.1278G>A, c.1369_1370insGGGTC, с.1570G>A, с.1973_1974delTC, c.2806A>T, с.2991-1G>C, c.3158C>G, с.3526_3528delAGA, с.3826delC, с.4514+5G>A, с.4537С>Т, c.5758_5761delTTGA, с.6792С>A) in 20 patients with NF1. We determined the random distribution of the types of mutations and did not reveal the specific features of the NF1 clinic depending on the type of mutations.

Conclusions. The protective role of crossbreeding in relation to brain cysts, as well as the predominance of skeletal anomalies in patients with NF1 inheritance from the mother, indicate the role of modifier genes in the pathogenesis of the disease. The identified mutations in the NF1 gene will allow us to perform prenatal prevention of NF1 in RB patients.

Introduction. Currently, there are conflicting data regarding the effect of the c.470T> C germline mutation in the CHEK2 gene on increasing the risk of breast cancer (BC), so it is necessary to conduct research on large samples of patients, including in the Russian population, in order to analyze the contribution of this mutation to the risk of cancer developing.

The aim of the study was to determine the frequency of occurrence of the genetic variant c.470Т>С in the CHEK2 gene in the Russian population in patients with BC and patients with benign breast diseases (BBD) to assess the possible effect of this deoxyribonucleic acid damage on the likelihood of cancer occurrence.

Materials and methods. The study included 2,787 patients with BC and 1,004 patients with BBD who underwent examination and treatment at the Russian Scientific Center of Roentgenoradiology of the Ministry of the Russian Federation from 2010 to 2018. Molecular genetic study was carried out by real-time polymerase chain reaction to determine the characteristic of the Russian population hereditary genetic variant c.470Т>С in the CHEK2 gene using a diagnostic panel that allows to determine three germline mutations: c.1100delC, c.444+1G>A and c.470Т>С in the CHEK2 gene.

Results. In patients with BC the frequency of the mutation c.470T>C in the CHEK2 gene was 3.8 %, in patients with BBD this mutation was detected in 4.7 % of cases. The frequency of the genetic variant c.470T>C in high-risk groups was: 5.1 % – for BC patients with clinical signs of hereditary disease and 4.9 % – for patients with BBD with a family history of cancer. There were no statistically significant differences between the frequency of the mutation c.470T>C in the general groups of BC patients and patients with BBD and the corresponding frequency in the high-risk groups, as well as in the groups of BC patients and patients with BBD (p >0.05).

Conclusion. The results of this study indicate the probable absence of a relationship between the presence of the mutation c.470Т>С in the CHEK2 gene and an increased risk of BC.

Background. Glioblastoma multiforme (GBM) develops in the hypoxic microenvironment, which plays an important role in the pathogenesis of the disease and is closely associated with tumor growth, development and poor prognosis. Hypoxia increases the resistance of tumor cells (TC) to radiation therapy and chemotherapy, promotes the appearance of an aggressive TC phenotype, leading to the disease recurrence. The molecular mechanism of hypoxic action on the secretome of GBM cells, which is involved in the formation of the tumor microenvironment, remains unclear. Also, markers of the aggressive hypoxia-associated phenotype of tumor cells have not been established.

 The purpose of research – to study the molecular mechanisms of the hypoxia-associated effect on the secretome of the U251 GBM cells.

Materials and method. High resolution proteomic mass spectrometry, cell technologies.

Results. A total of 1432 proteins were identified in the secretomes of two types of GBM cells (control and experiment). After the action of hypoxia, statistically significant changes in the expression of 390 proteins were registered. 11 proteins showed increase in expression over two orders of magnitude. The intracellular signaling pathways which are responsible for the hypoxia-associated effects on the U251 GMB cells have been identified.

Conclusions. Hypoxia significantly affected the proteomic composition of the GBM cells secretome. Five overexpressed secretome proteins, S100A6, HEY1, ZIP3, S100A4, ZEB2, have been proposed as potential markers of the hypoxiaassociated phenotype of GBM, for which participation in the pathogenesis of glioblastoma multiforme has been previously showed.

Background. Recent data show evidence that lipid rafts (LR) proteins could be involved in the formation of exosomes and the sorting of proteins that make up the exosomal cargo. Such data are available for flotillins, structural and functional components of flatted rafts. The presence of the main component of caveolar rafts, caveolin-1 (Cav-1), has been shown in exosomes produced by some cancer cells; however, its possible participation in the regulation of the protein composition of exosomes has not been studied previously.

Materials and methods. Knockdown of Cav-1 by transduction of a lentiviral vector expressing precursors of short hairpin ribonucleic acid to Cav-1; isolation (by ultracentrifugation) and analysis (transmission electron microscopy, nanoparticle tracking analysis) of extracellular vesicles (EVs) from non-small cell lung cancer cells (NSCLC) H1299; analysis of proteins in cells and in EVs by immunoblotting.

Results. Analysis of the effect of Cav-1 expression on the composition of EV proteins associated with exosome biogenesis revealed a decrease in the level of Alix and TSG101, an increase in the level of LR proteins and the absence of changes in the level of tetraspanin CD9.

 Conclusion. The obtained data demonstrate a Cav-1-dependent changes in the composition of EVs, indicating a change in the ratio of vesicles formed by the various molecular mechanisms.