The transformation of normal precursors into cancer cells is an intricately regulated, multistep process. The master regulatory genes that play a crucial role in the process of organism development may also play a key role in carcinogenesis. From such a point of view, cancer is not simply a genetic disease that is due to a progressive accumulation of mutation--it is also a disorder of the developmental system of the tissue in which cancer emerges. Master regulators and their genes disturb stem cell differentiation upon mutation and thus may serve as targets for cancer therapy, in addition to the classic oncogenes and suppressors of tumor formation. This review is an attempt to give a modern concept of master genes and their functions in adult stem cells of the organism and in carcinogenesis, with pancreatic cancer as an example.

The dogma of the central nervous system (CNS) as an immune-privileged site has been substantially revised in recent years. CNS is an immunocompetent organ and actively interacts with the immune system. Microglia plays a leading role in a CNS immune response. However, in malignant gliomas, there is M2-polarization of microglia acquiring immunosuppressive and tumor-supportive properties. It occurs under the influence of tumor cytokines, such as transforming growth factor-β, interleukin-10, and prostaglandin E2. M2-polarized microglia exhibits reduced phagocytic activity, changes in the expression of many cellular determinants, or inverse of their functions, STAT3 activation, and production of immunosuppressive cytokines that suppress the function of cytotoxic CD8+ T cells or CD4+ T-helper cells type I. Myeloid-derived suppressor cells and regulatory T-lymphocytes, which have been recruited from peripheral blood into tumor tissue, also have immunosuppressive properties. The development of new treatment options for malignant gliomas must consider the role of the microenvironment in maintaining tumor vitality and progression.

Suppression of resistance in acute myeloid leukemia cells to TRAIL-induced apoptosis in multicellular aggregates, was studied using small molecule inhibitors of the activation of the transcription factor NF-kB - NF-k9 Activation Inhibitor IV and JSH-23 at non-toxic concentrations. NF-kB Activation Inhibitor IV and JSH-23 reduced resistance in the acute myeloid leukemia cells in multicellular aggregates to cytotoxic action of recombinant protein izTRAIL. It is shown that the use of these inhibitors decreased the phosphorylation of the RelA (p65) as a main marker activation of the transcription factor NF-kB. We discuss a possible reason for increasing resistance in acute myeloid leukemia cells to TRAIL-induced apoptosis in multicellular aggregates.

Risk factors related to secondary oligomenorrhea (SOM) are the presence of chronic extragenital pathology, abrupt changes in body mass during a short period of time, a burdened perinatal history at the onset of SOM after a year of regular menstruations. Adolescent girls with SOM differ from their healthy peers by a frequent occurrence of hirsutism, obesity and body mass deficit, uterine hypoplasia.

Targeted delivery of semiconductor quantum dots (Q Ds) to tumors overexpressing HER2 cancer marker has been. demonstrated on immunocompromised mice bearing human breast cancer xenografts. To obtain targeted QDs complexes we applied the approach based on the use of protein adaptor system, RNAase barnase and its inhibitor barstar. Specific binding to target cancer marker was achieved through bivalent fusion protein containing two fragments of4D5scFv recombinant antibody and a fragment of barnase. QDs were conjugated to barstar, and final assembly of targeted complexes was obtained through non-covalent specific interaction of barstar, attached to QD, and barnase, that is part of the recombinant targeting protein. The efficient delivery of QDs to HER2-expressing tumor demonstrates the possibilities and prospects of the approach for targeted delivery of nanoparticles to cancer cells in vivo as the way to improve the efficiency of diagnosis and promote development of therapies based on the use of nanoparticles.

The HER2/neu receptor is over-expressed on the surface of many types of cancer cells, and is widely used for tar- geted delivery of anticancer drugs. We have created geneti- cally engineered construct expressing the PE40 fragment of Pseudomonas toxin bound with the DARPin molecule which recognizes the HER2/neu receptor with high specificity. The construct destroyed transfected tumor cells in vitro. Intra-tumor injections of the construct complexed with polyethyleneimine led to growth retardation of D2F2/E2 tumors in mice. These results suggest a possibility of using this approach to develop new anticancer drugs.

One of the risk factors for the development of malignant tumors, including prostate cancer, is an individual genetic predisposition due to the various unfavorable polymorphic variants of normal genes. The aim of the study was to com- pare the frequency of different genotypes of polymorphic vari- ants of genes CYPJA2, GSTT, GSTM, GSTP1 (xenobiotics detoxification), XRCC1, XRCC3,(DNA repair) and VDR, AR (transcription factors) in patients with prostate cancer and in control group to determine their association with genetic pre- disposition to this disease. According to the results obtained the rs1544410 AA genotype (VDR gene) and the presence of less than 20 CAG repeats in the 1st exon (AR gene) are the risk factors for the development of prostate cancer. The het- erozygous genotype 722 CT (XRCC3 gene) demonstrated the protective effect.

The significance of quantitative changes of ALDH1A1 and RDH10 gene expression in 22 non-treated multiple myeloma patients were studied. We found a direct correlation between the expression of ALDH1A1 and RDH10 genes. We showed that ALDHA1 and RDH10 expression were inversely related with expression of a key gene for all-trans-retinoic acid catabolism, CYP26A1, and correlated with expression of RARα and PPARβ/ genes. In addition for the first time it was re- vealed that increased expression of ALDH1A1-RDH10-RARα- PPARβ/δ pattern could be considered as adverse prognostic factor associated with a higher concentration of paraprotein and worst overall survival of patients with newly diagnosed multiple myeloma.

Retrotransposons are the mobile part of the genetic material in mammals. Such a close proximity is a unique in its kind example of the genetic symbiosis. As a result of long-term co-evolution retroviruses purchased the actual immortality and protection from adverse factors, providing instead the recombinant opportunities of its genetic apparatus for the implementation of the evolutionary, adaptive and biological processes that are vital to the host organism. The consequence of the violation of the established biological balance is the pathological activity of retrotransposons that can affect the expression of any gene. This review examines the point of view on the key role of retrotrasposons in the biology of tumor development as a result of aggressive parasitism and speculates about the causes of the violations of adequate immune response in the process of tumor growth.

CHEK2 is classified as a moderate-penetrance gene for hereditary breast cancer (BC). In Russia, CHEK2 mutations hold second position in the list of BC-predisposing gene defects after BRCAl, and include CHEK2 1100deIC, de15395, and IVS2+lG>A gene-inactivating alleles. CHEK2-driven breast carcinomas are generally characterized by poor prognosis and low sensitivity to the conventional therapeutic regimens. CHEK2 testing needs to be incorporated into routine clinical practice owing its overt clinical significance.

Whole exome sequencing (WES) has become a leading tool for genetic analysis right after its invention. This approach permits the detection of mutations spread within coding regions of the entire genome. For cancer patients WES is particularly effective for the search of hereditary cancer mutations and identification of somatically mutated druggable genes. Use of WES already resulted in significant advances in understanding for molecular mechanisms of cancer.

Liquid biopsy is a promising approach to molecular tumor testing in the context of targeted therapy. During this pilot study we applied a high-sensitivity protocol for detection of tumor-derived mutations in circulating plasma DNA of EGFR-positive non-small cell lung cancer (NSCLC) patients during EGFR-TKI therapy. We showed that this protocol was well suited for dynamic monitoring during targeted therapy as well as for detection of acquired resistance mutations.

The role of infection in the beginning and progression of prostate cancer is not known to the end at the moment. Experimental data, presented in the article, are obtained by hybridization in situ and demonstrate high degree of infection of the prostate tissue by viruses with the oncogenic and oncomodulation properties HCMV, EBV, HHV8 and HPV. The authors revealed that in patients at different substages of T2 stage infection of the prostate tissue increased from T2a to T2c. The importance of these findings is discussed.

We examined 100 patients with non-small cell lung cancer (NSCLC). In addition to surgery there was performed neoadjuvant chemotherapy (2-3 cycles) EP (cisplatin at a dose of 80 mg/m2 on first day + etoposide at a dose of 120 mg/ m2 on days 1,3,5). There were studied the levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) as prognostic factors in the use of neoadjuvant chemotherapy in patients with NSCLC. The control group consisted of 30 healthy volunteers. The baseline level of bFGF was necessary for the prediction of combined treatment in patients with NSCLC stage III. The threshold value bFGF>10,2 ng/ml allowed predicting a good effect from chemotherapy with a sensitivity of 71,4% and specificity of 80,6%, while the sensitivity of VEGF in terms of forecasting bicycles reached 42,9 %. The resulting algorithm for predicting of the effect of neoadjuvant chemotherapy of patients with NSCLC provided perspectives to improve the outcomes of such patients.

There were analyzed epidemiological risk factors in 505 breast cancer patients receiving treatment in the Tashkent City Oncology Dispensary. The tumor was studied by the hormone-receptor status, the level of Her2/neu protein hyperexpression and proliferation index in tumor cells Ki 67. The risk of developing breast cancer was higher in women aged 40 to 60 years with the most adverse prognostic biological subtypes of breast cancer. The high incidence of hypothyroidism along with established epidemiological risk factor for breast cancer, such as obesity, was investigated.

There was conducted a study of edematous-infiltrative form of breast cancer in comparison with other forms of locally advanced breast cancer in various molecular-biological parameters. It was provided an evaluation of expression of receptors of steroid hormones, mutational status of HER2/neu gene, mutation status of ALK gene (a number of copies of a gene, translocation of EML4-ALK, point mutations in exons 22-25). There were studied mutational changes of genes of signaling pathway PIK3-AKT-mTOR (point mutations in exons 9 and 2° of PIK3CA gene and 4 in exon of AKT gene), mutations in exons 5-8 of p53 gene. It was found that in edematous breast cancer significantly more frequently there were met tumors with negative receptor status (p = 0.006) and a positive HER2/neu status (p<0,001). In 5% of patients with edematous-infiltrative breast cancer there was detected translocation of EML4-ALK (p = 0.045), while it was not found a single case of ALK gene amplification. In the analysis of PIK3CA gene it was revealed that significantly frequently mutations localized in exon 9 (p = 0.038). There were no statistically substantial differences in the number of point mutations of p53 gene between a grou of edematous-infiltrative breast cancer and a control group.

Glioblastomas are characterized by a variety of genetic and epigenetic disorders, identification of which allows constantly expanding a list of genes directly involved in carcinogenesis, thus increasing molecular diagnostics, monitoring and predicting disease. Molecular-genetic studies of patients with glioblastomas allowed revealing changes relevant to this disease and determining their prognostic significance. In the future molecular-biological markers along with clinical and therapeutic factors may play a role of separate and independent factors of prognosis in patients with malignant brain lesions.

Study of cervical cancer patients with I-III stage was performed with biomarker determination of the blood DNA radiosensitivity ex vivo. The biochemical index was measured before treatment start during 4 hours by use fluorescent dye. The relationship between changes of these index levels and volume tumor reductions after radiochemical treatment evidenced that blood DNA radiosensitivity was enabled to predict an outcome of the cervical cancer patient treatment earlier than the assessment of therapy efficacy by help of ultrasound measurements.

Over the past decades the studies have greatly improved our understanding of the molecular basis of multiple myeloma (MM) and mechanisms of disease progression. The majority of the most widespread chromosomal aberrations, revealing in MM, has independent predictive value and influence on a choice of optimal treatment. There were observed 190 MM patients in hematologic hospitals of St. Petersburg. Genetic anomalies (GA) were detected at 3l,3% of patients and did not depend on their age. Patients with ISS III had a detectability of GA higher than with ISS II and ISS I (48,°% (24/5°), 2l,2% (7/33) and 27,6% (8/29)). Translocation t(ll;l4) was found in 23,3% (3O/129) patients; dell3q - 20,8% (27/13°); dell7p - at 8,4% (7/83); t(4;l4) - at 6,9% (9/13O), that allowed to stratify patients in groups of risk according to mSMART version l. O and 2. O. Median overall survival (OS) modified mSMART l. O in group of standard risk was 7° months, high risk - 47,l months. Median OS mSMART 2. O in group of standard risk was 7° months, intermediate risk - 47 months, high risk - 45 months. OS did not depend on age, clinical manifestations, treatment and other factors.

The discovery of the JAK2V617F mutation was the beginning of a new era in the study of myeloproliferative neoplasms (MPN). In addition to contributing to the understanding of the pathophysiology of Ph-negative MPN, JAK2 mutation has become a new therapeutic target in their treatment. In treatment of PV a new era began the era of targeted therapy, which gave a hope for better treatment outcomes and improved quality of life for patients who are resistant to standard therapy. This work presents literature data on molecular-genetic features of the pathogenesis of polycythemia vera (PV) and new possibilities in the treatment of this disease, literature review about JAKinhibitors, targeted therapy of PV. There are reviewed issues on resistance and intolerance of hydroxycarbamide and interferon (IFN-a) and the definition of the indications for administration of JAK-inhibitors. There are presented data on the efficacy and safety of ruxolitinib, which were proven within the clinical trial RESPONSE.