First time p53 was found in the complex with viral large T-antigene in the cells transformed by small DNA virus SV40. The cloning of p53 cDNA was done in the beginning of eighties and soon after that the whole p53 gene was cloned. The p53 family is comprised of three genes: TP53,TP63 and TP73, each of which is expressed as a set of structurally and functionally different isoforms. All of them intensively interact with each other forming a united functional network of proteins. In this review we discuss evolution of the p53 family and significance of all its members in embryonic development, reproduction, regeneration, regulation of aging and life span, as well as in the body's defense against cancer. With special attention we review the role of less studied members of the p53 family: p63 and p73, in oncogenesis and tumor progression and show that different isoforms of these proteins might exert a contrary effect on these processes.

Melanoma is a highly aggressive neoplastic disease attributed to transformed melanocytes. The efficacy of regimens of cytotoxic chemotherapy for advanced stage patients does not exceed 20%. Search for lymphocyte markers of patients' sensitivity to chemotherapy provides a rational basis for development of cytotoxic chemotherapy. Using blood lymphocytes we evaluated efficacy of BER and MMR, expression of MLH1, MSH2 and FasR, and cell death in melanoma patients relative to clinical response to chemotherapy. We found that LDCI-chemotherapy (lomustine, dacarbazine, cisplatin and interferon gamma), induced AP sites and DNA ss-breaks which repaired trough BER pathway. However, neither initial DNA damage nor the rate of their repair correlated with clinical response. This result prompts us to think that this type of damage is not crucial in cytotoxic effect of LDCI-regimen of chemotherapy. DNA ds-breakes appeared downstream ss-breakes were attributed to repair of 06-methylguanine by MMR mechanism in PHA-stimulated lymphocytes. The number of ds-breakes appeared by 48 correlated with positive clinical response of patients to chemotherapy. The same link was observed between clinical response and the number of dead lymphocytes. However, there was no correlation between clinical response and expression of MLHI + MSH2 and FasR. These results imply possible contribution of crosslink repair through NER pathway to formation of DNA ds-breaks as well as to cytotoxicity of LDCl-therapy. The observed link between high level of secondary ds-breaks and positive response to chemotherapy indicates the potential of these instruments to serve as prognostic end point in clinical trials.

To study distribution of some karyotype variants among patients of different age with acute myeloid leukemia (AML).

The frequencies of the polymorphic gene variants MnSOD Ala9Val, GPX1 Pro198Leu, and GSTP1 Ile105 Val were estimated in female residents of Altai krai with breast cancer. The frequency distributions of the genotypes for all genes studied in both patients and control subjects fit the Hardy-Weinberg equilibrium. The estimated frequencies of the genotypes for the studied genes in the control group did not differ from those earlier reported for Caucasoid women living in Europe. The T(rs1050450) allele of the GPX1 gene was demonstrated to protect against sporadic breast cancer (OR = 0.74 (95% CI = 0.58-0.94), p = 0.012). Carriers of the genotype combination MnSOD CC + GPX1 CC were found to have a 1.6 times higher risk of sporadic breast cancer compared to the control group (OR = 1.59 (1.05-2.41), p = 0.0258). The polymorphic loci GSTP1 (rs1695) and MnSOD (rs4880) were not found to be significantly associated with the risk of familial or sporadic breast cancer.

Current recommendations for limiting exposure to ionizing radiation are based on the linear-no-threshold (LNT) model for radiation carcinogenesis under which every dose, no matter how low, carries with it some cancer risk. In this review, epidemiological evidences are discussed that the LNT hypothesis is incorrect at low doses. A large set of data was accumulated that showed that cancer risk after ordinarily encountered radiation exposure (natural background radiation, medical X-rays, etc.) is much lower than projections based on the LNT model. The discovery of the low-level radiation hormesis (stimulating effect) implies a non-linear dose-response curve in the low-dose region. The further studies in this field will provide new insights about the mechanisms of radiation carcinogenesis.

One of the key stages of life of a cell is genome duplication. The main enzymes which lead this process are DNA-dependent DNA polymerases. At the moment, 19 DNA polymerases with striking properties are listed in the eukaryotic cells. Mitochondrial DNA polymerase gamma from A family and most of the nuclear enzymes from B family are high fidelity DNA polymerases which are participate in genome DNA replication process as well as in DNA repair. Among the other 1 5 proteins, the D N A polymerases belonging to the X and Y families have a special place. They participate in a different repair processes such as base excision repair and non-homologous end joining. Moreover, some of them play a specific role in the replication of the damaged DNA templates. This process is referred as translesion synthesis or TLS. The DNA polymerases beta and lambda members of X family are enclosed in polyfunctional enzymes, and their properties and functions will be discussed in this review.

The molecular-cellular parameters complex has been studied on the blood lymphocytes of malignant Hodgkin's lymphoma (HL) patients: the frequency of cells with micronuclei (MN) and chromosome aberrations; the level of DNA single and double strand breaks - OR and DR DNA (DNA comet assay), oxidative status--the content of reactive oxygen species (ROS) by using nonfluorescent dye that is oxygenated in the cells to fluorescent reagent and detection of fluorescence intensity after there. It was shown that the patients with LH had the increased level of DR and OR DNA, the increased frequency of cells with chromosome aberrations and the number of aberrations per cell was increased too. The concentration of ROS is increased too for the most individuals with intoxication. In the process of the chemical and radiation therapy the increase of OR DNA level, the frequency of the cell with MN has been registered. The ROS concentration correlates with the level of DNA-strand breaks. So the blood lymphocytes of HL patients before treatment differ from the lymphocytes of healthy donors. The damage of genome and the change of oxidative status have been observed that can be additive markers for the HL diagnosis, their sensitivity to the treatment and the characteristic of lymphocytes changes by this disease.

Summarised data about polymorphism of xenobiotic metabolism enzyme system (XMES) have been presented. Metabolic molecular mechanisms and the role of genetic polymorphism in metabolic transformation of different xenobiotics are reviewed. Significance of X-transport proteins and nuclear receptors in regulation of XMES-activity are discussed. Possible connection of XMES polymorphism with the development of cancer was examined. Experimental modeling of different levels of epoxide syntase and epoxide hydratase activites has revealed their connection with cancer development. Physiological factors should be considered when evaluation of risk extent for cancer development is carried out.

Polymorphic variants of cytochrome P4501A1 (CYP1A1), glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) distribution was studied in patients with chronic myeloid leukemia (CML) and healthy individuals. It was shown that homozygotes for the GSTT1 gene deletion occur significantly more frequently in the CML patient group compared to the control group (13.17% versus 24.10% in CML patients, Chi2 = 4.40, p < 0.05; OR = 2.09; 95% CI = 1.10-3.99). In contrast, no significant difference was observed between the healthy individuals and CML patients in the frequency of polymorphic variants of GSTM1 and CYP1A1 genes (p > 0.05).

Fluorescent in situ hybridization (FISH) is a valuable tool for detection of chromosome aberrations in clinical practice of malignancies. However, the relatively high false positive and false negative rates of this method complicate its application to analysis of small populations of pathological cells. Combined simultaneous analysis of morphology and FISH using a Duet multiparametric cell scanning system (BioView, Rehovot, Israel) has been developed and introduced into clinical practice. The novel method has been demonstrated to increase the specificity of identification of pathological cells inpatients with various hematological malignancies and, hence, estimate the efficiency of treatment. Studies on different premalignant disorders of the oral cavity mucosa have demonstrated that the combined method allows the identification of individual pathological cells and, hence, early detection of malignant and premalignant cells that may be overlooked by traditional histomorphological methods.

Metastasizing is one of the key stages in tumor development. Understanding this process is necessary for effective diagnosis, therapy and prediction of clinical outcome. Some recent data suggest the possibility of metastatic phenotype cells appearance at the early stages of tumor evolution in contravention with generally accepted hypothesis of linear metastatic process development. In this study we have performed a comparative analysis of the array-based DNA methylation profile in biopsy samples of patients with benign breast disorders, breast cancer and lymphogenous metastases. In some cases the biopsy samples dated back to different stages of the same tumor. For the analysis the GoldenGate Methylation Cancer Panel I was used. The DNA methylation level in 1,505 CpG-sites was similar in samples from patients with benign breast disorders and lymphogenous metastases. Our data support the hypothesis of the early appearance of cell clones responsible for the tumor limphogenous dissemination. Epigenetic component apparently plays an important role in this process.

Li-Fraumeni syndrome (sarcoma family syndrome, OMIM 151623) is a rare clinically and genetically hetergoeneous autosomal dominant disorder characterized by the evolvement and accumulation of soft-tissue osteogenic sarcomas in members of a family, as well as uni- and bilateral breast cancer in young women, brain tumours, adrenocortical cancer, and lymphoproliferative diseases. Germinal mutations of the TP53 gene constitute the etiological genetic basis of Li-Fraumeni syndrome. American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network developed recommendations for genetic testing and observation of carriers of TP53 mutations. In vitro and in vivo studies demonstrated correlation between the TP53-mutant genotype and resistance to standard therapeutic modalities. This finding gave impetus to the development of new genotherapeutic approaches to the treatment of TP53-associated tumours in patients with Li-Fraumeni syndrome.

Familial (hereditary) cerebral cavernous malformations (CCM) are rare disorders, they have autosomal-dominant type of inheritance. We report 12 families of non-Hispanic descent in which 54 typical CCM were discovered. In 8 families CCM were identified in 2 generations, in 2 - in 3 generations. 46 lesions were supratentorial, 8 - subtentorial. Multiple lesions were present in 67% of cases. Manifestation was observed in 24 persons, including seizures in 17 and hemorrhage in 7. In 9 of 10 families onset of symptoms was earlier with every next generation. In one patient asymptomatic parietal CCM was associated with symptomatic posterior fossa AVM and cutaneous angioma. On the follow-up MRI revealed no new lesions. Surgical treatment was performed in 14 cases: in 13 patients 15 CCM were removed, and 1 patient underwent third ventriculostomy. The paper discusses evaluation and management of families with symptomatic and asymptomatic types of disease, trends and perspectives of further investigations.

Embryonic tumor with abundant neuropil and true rosettes (ETANTR) is a very aggressive rare tumor with unique histologic and molecular features occurring in very young children. At present approximately 80 cases of ETANTR have been documented in the literature since first description in 2000. We report seven patients with ETANTR below 4 years of age who underwent surgical resection in the Burdenko Neurosurgery Institute between 2005 and 2010. Four children have received different modality chemotherapy and radiotherapy and two patients were treated by chemotherapy alone. One child did not receive any adjuvant treatment. All children had local relapses, two of them were operated twice. A 2 year old girl underwent subtotal resection thrice. Histological examination showed that all tumors were composed of true multilayered rosettes admixed with large areas of paucicellular neuropil. By analysis of recurrences we have found that large areas of neuropil and number of true rosettes were lost and tumors acquired a resemblance to central nervous system primitive neuroectodermal tumors. In four cases frozen tumor material was available for array-based comparative genomic hybridization, which discovered trisomy of chromosome 2 and amplification at the 19q13.42 chromosome locus. Fluorescence in situ hybridization revealed amplification at the 19q13.42 chromosome locus in all cases.

We carried out comparative morphometric and densitometric analysis of cell nuclei in pancreatic intraductal papillary mucinous tumors. Proliferative activity values, aneuploidy coefficient, and histogram of nuclear DNA content are recommended as additional criteria for the diagnosis of tumor malignancy.

Comparative morphometric and densitometric studies of cell nuclei in endocrine tumors of various differentiation degree and endocrinocytes of Langerhans islet in the adjacent pancreatic tissue were carried out. Index of proliferative activity, aneuploidy coefficient, and histogram of nuclear DNA content are recommended as additional criteria for the diagnosis of endocrine tumor malignancy.

In the present study we have applied the siRNA approach for substantial reduction of AML1-ETO and RUNX1 (K83N) expression, which are frequently found in the leukemic cells. We have designed small hairpin RNAs (shRNA) for targeting AML1-ETO oncogene and a region close to the 5'-untranslated region of mRNA for the mutant RUNX1 (K83N) oncogene and expressed the shRNAs in lentiviral vectors. We report a stable reduction in expression of the oncogenes following the introduction of shRNAs into cells.

Breast cancer is the most incident cancer among women. We investigated the role of polymorphisms of folate metabolizing genes MTHFR (C677T and A1298C), SHMT1 (C1420T) and MTHFD (G1258A) in genetic susceptibility to this type of cancer. We determined allele and genotype frequencies in case (850 women with sporadic form of breast cancer) and control (810 women) groups. None of these polymorphisms was significantly associated with breast cancer risk. To increase statistical power of our study, we conducted a meta-analysis which included published genotype data and the results of our work. Meta-analysis also revealed no significant association of studied SNPs with breast cancer.