Recent large-scale genomic studies established the occurrence of multiple DNA sequence variants in genomes of healthy individuals that differ from the reference sequence. Among these variants mostly represented by germline single nucleotide polymorphisms disease-related alleles are detected including alleles which are associated with monogenic disorders, and putative deleterious genetic variants. Apart from functional significance of a particular variant and of a gene harboring it, the penetrance of these allelic variants depends on their expression level and can be determined by preferential expression of a particular allele, or allele-specific expression. It is estimated that 20–30 % of genes present in the human genome display allelic bias in a tissue-specific manner. Allele-specific expression is defined by a range of genetic and epigenetic mechanisms including cis-regulatory polymorphisms, allele-specific binding of transcription factors, allele-specific DNA methylation and regulation through non-coding RNA.

Although the data on the issue are scarce, allele-specific expression has been reported to be implicated in several hereditary disorders including benign and malignant tumors of the large intestine. Recent studies that estimate allele-specific expression incidence in tumors and identify wide range of genes displaying allelic imbalance indicate that allele-specific expression might play a significant role in carcinogenesis. Eventually, estimation of transcriptional rate of allelic variants which cause dysfunction of oncogenes and tumor suppressors may prove to be essential for rational choice of antitumor therapeutic strategy. In this review, we outline the main concepts and mechanisms of allele-specific expression and the data on allelic imbalance in tumors.

Findings in experimental oncology in beginning of last century and subsequent achievements of genetics of tissue compatibility resulted in divergence of transplantational immunology and oncoimmunology. However, central achievements of both scientific fields are based on unified phenomenon of interaction between T-cell receptor (TCR) and histocompatibility molecules. In this review we describe the history of ideas, achievements and unique experience of the team of the Laboratory of Regulatory Mechanisms in Immunity at Scientific Research Institute of Carcinogenesis, N.N. Blokhin Russian Cancer Research Center for all time of existence. This experience shows that efficiency of immunological defense including immunological surveillance are critically influenced by T-cell receptor repertoire. Transgenesis of individual chains of TCR is one of possible means to manage T-cell repertoire. Functional outcomes of transgenesis may be different due to diverse extent of dependence of α- and β-chains expression on the rules of allelic exclusion. Expression of transgenic β-chains results in the expansion of TCR repertoire diversity. Expression of β-chains is under strong control by allelic exclusion, resulting in formation of repertoire bearing mainly invariant transgenic β-chain pared with different α-chains and overall narrowing of repertoire. Earlier, we cloned genes encoding α- and β-chains of TCR of CD8+ memory cells specific to histocompatibility molecule H-2Kb . After introduction them in zigotes we have obtained transgenic mouse strains, which could be used for modeling of interactions between tumor cells and immune system of recipient. Normally, B10. D2 (R101) mice reject lymphoma EL4 cells in 12–14 days after transplantation, in spite of the fact, that allogeneic difference between B10. D2 (R101) (Kd Id Db ) mice and lymphoma EL4 (H-2b) cells is only in one product of MHC, the H-2Kb molecule. Transgenics carrying β-chains of TCR displayed compromised immunity to tumor cells resulting to their long persistence, tumor progression, the loss of H-2Kb molecule and death in 2–3 months after transplantation. This model allows to see all three phases of interaction between tumor and immune system of recipient – elimination, equilibrium and escape. Against, transgenics carrying α-chain reject tumor cells much more quickly, as in secondary immune response, in 3–6 days after transplantation. This rejection was mediated by intraepithelial T lymphocytes displaying features of resident memory cells – inability to recirculation, expression of CD103 and early activation antigen CD69 and intermediate density of T-cell markers CD3 and CD8. The capability to be located in nonlymphoid tissue and quickly destroy tumor cells makes them to be the most probable candidate to perform immunological surveillance functions.

Wnt cascade is one of the most important signal pathways in the cell, which is required for normal embryonic development, differentiation, maintenance of stem cell phenotype and migration. Mutations in this pathway are associated with tumor growth (especially with colon cancers, hepatocarcinomas and leukemias), where they participate in maintenance of tumor-initiating cells and metastasing. Because of that there is a considerable interest to develop inhibitors of Wnt pathway as anti-tumor agent. But this inhibitors are still only in early stages of clinical investigations. In this article we review the main targets for this anti-cancer agents and their preclinical and clinical status.

Neuroblastoma, the most common extracranial tumor of childhood, arises from the developing neurons of the sympathetic nervous system (neural cress stem cells) and has various biological and clinical characteristics. The mean age at disease onset is 18 months. Neuroblastoma has a number of unique characteristics: a capacity for spontaneous regression in babies younger than 12 months even in the presence of distant metastases, for differentiation (maturation into ganglioneuroma) in infants after the first year of life, and for swift aggressive development and rapid metastasis. There are 2 clinical classifications of neuroblastoma: the International neuroblastoma staging system that is based on surgical results and the International Neuroblastoma Risk Group Staging System. One of the fundamentally important problems for the clinical picture of neuroblastoma is difficulties making its prognosis. Along with clinical parameters (a patient’s age, tumor extent and site), some histological, molecular biochemical (ploidy) and genetic (chromosomal aberrations, MYCN gene status, deletion of the locus 1p36 and 11q, the longer arm of chromosome 17, etc.) characteristics of tumor cells are of considerable promise. MYCN gene amplification is observed in 20–30 % of primary neuroblastomas and it is one of the major indicators of disease aggressiveness, early chemotherapy resistance, and a poor prognosis. There are 2 types of MYCN gene amplification: extrachromosomal (double acentric chromosomes) and intrachromosomal (homogenically painted regions). Examination of double acentric chromosomes revealed an interesting fact that it may be eliminated (removed) from the nucleus through the formation of micronuclei. MYCN oncogene amplification is accompanied frequently by 1p36 locus deletion and longer 17q arm and less frequently by 11q23 deletion; these are poor prognostic factors for the disease. The paper considers in detail the specific, unique characteristics of the biological behavior of neuroblastoma, which are untypical of other tumors; histological structure; determinants of the prognosis of the disease, including MYCN gene status; and mechanisms for formation of the amplification and elimination of amplified sequences from the nucleus.

Relevance. Breast cancer is the most commonly diagnosed cancer in women. Tumor biopsy, a key diagnostic approach, is required to evaluate the nature of tumor and to determine the therapeutic strategy. In clinical practice methods are being applied: trepan-biopsy and fine needle aspiration biopsy (FNAB). The latter is less traumatic however is used less often because it provides with less information. Moreover, dependence from quality of biopsy and qualification of morphologist are attributes of both techniques. A possibility to use biopsy material for farther analysis of tumor-markers would open a perspective to obtain more information and to improve objectivity of traditional diagnostic approaches, including FNAB. MicroRNAs (miRNAs), regulatory molecules involved in control of virtually all physiologic and pathologic process, emerged as promising tumor markers. Malignant transformation of mammary gland epithelia is associated with specific alterations of cellular miRNAs profile. Analysis of these alterations is of great diagnostic potency.

Objective. Development of method for miRNAs analysis in cytological smears material and evaluation of its practical applicability.

Material and methods. Archived cytological material (smears on the glass slides) from patients with benign tumor and breast cancer was used. Analysis of miRNAs expression was performed by reverse transcription followed by quantitative PCR. Results of reverse transcription polymerase chain reaction were analyzed with use of relevant cytological and morphological data.

Results. Method of miRNAs analysis in material of cytological smears was developed. Expression of 9 miRNAs in 80 samples was evaluated. Statistically significant expression difference between benign and malignant tumor samples was found for 5 miRNAs: miR-21, miR-205, miR-125b, miR-200a, miR-221. MiR-125b exhibited most prominent expression dysregulation: malignant transformation of mammary epithelium is associated with 500 fold decrease of miR-125b expression level. Expression alterations of several miRNAs were revealed to correlate with clinically relevant characteristics of tumors.

Conclusions. Results of our study indicated the possibility of miRNAs expression analysis in the FNAB material and the applicability of this method as additive approach to the convention cytological examination. Application of this method will allow to specify diagnosis and to optimize choice of the therapeutic strategy.

Background. Proteoglycans (PGs) are complex glycosylated molecules playing an important role in cell-cell and cell-matrix interactions and signaling. Expression of PGs and their expression pattern change considerably during malignant transformation of mammalian cells and tissues.

Objective. The aim of our work was to investigate tissue-specificity of main PGs expression (glypican-1, perlecan, syndecan-1, aggrecan, versican, CSPG4/NG2, brevican, decorin, lumican) in normal cells (fibroblasts and normal epithelial prostate cells PNT2) and in different human cancer cell lines (prostate, breast, lung, brain, kidney). Expression patterns of main PGs were determined in these cells using reverse transcription polymerase chain reaction analysis and immunocytochemical staining.

Results. It was shown that fibroblasts actively expressed PGs, and PNT2 cells had lower (5–6-fold) expression levels of a limited set of PG. In different cancer cell lines, overall transcriptional activities of PGs varied up to 10-fold, although their expression patterns had tissue-specific properties (for example, expression of syndecan-1 is more specific for prostate cancer cells, while perlecan is typical for lung cancer cell lines).

Conclusions. Along with this, variability of the PG expression patterns in cell lines of the same tissue of origin was shown, suggesting a possible contribution of the variable PGs expression to intratumoural heterogeneity of cancer cells and their potential as perspective biomarker (s) for personalised cancer diagnostics.

4 февраля 2016 г. после тяжелой продолжительной болезни на 76-м году жизни скончался Фёдор Львович Киселёв, выдающийся вирусолог, ученый с мировым именем, долгое время руководивший отделом трансформирующих генов опухолей Научно-исследовательского института канцерогенеза Российского онкологического научного центра им. Н.Н. Блохина, профессор, член-корреспондент РАН.