REVIEW ARTICLES
Despite the sufficient amount of data accumulated in the literature, there are still no factors, on the basis of which it would be possible to estimate the regional lymph nodes status in breast cancer with a high degree of accuracy. The review presents literature data relating to the influence of clinicopathological, molecular-biological and genetic characteristics of primary tumor on lymph node metastases. Data of 66 foreign and Russian articles are included.
The prospects of treatment strategies for patients with non-small cell lung cancer (NSCLC) featuring the acquired resistance to tyrosine kinase inhibitors, not associated with the Т790М mutation, are quite vast from a scientific point of view, but in routine clinical practice they are not yet available in full. Understanding the mechanisms of acquired resistance to tyrosine kinase inhibitors is important for clinicians from the perspective of the possibility of forming more effective options for the second and subsequent treatment of NSCLC. The most studied and frequent mechanism causing the formation of the acquired resistance is the appearance of the Т790М mutation in 20 exons of the EGFR gene. This article describes the current understanding of the mechanisms of acquired resistance to tyrosine kinase inhibitors not associated with the mutation of T790M, the evolution of views concerning the treatment of NSCLC, progressing in the course of the treatment by this group of drugs. Taking into account the diversity of unresolved issues and directions of further scientific research, we should not forget about the available research results and the ability to use the described options in routine clinical practice in a proper way.
The number of healthcare workers is over two million in Russia. Many of them are exposed to hazardous physical, chemical and biological occupational factors acting along with psychological strain. The results of large epidemiological studies carried out in various countries revealed greater cancer risk in physicians and nurses: cancer of the breast, skin, brain and other sites. Higher cancer risk of lung, breast, uterine, ovary, brain is considered to be associated with ionizing radiation. The female healthcare workers who handle antineoplastic drugs showed a greater risk of birth defects in offspring, spontaneous abortions and breast cancer. In Russia, the growing number of accidents among healthcare workers following transmission of infection by carcinogenic biological factors such as HBV and HIV is observed. Higher risk of reproductive impairments, hyperplasia of the breast and uterine tissues, breast cancer are revealed in nurses working the night shift. In Russia, there is lack of epidemiological studies of cancer risk among healthcare workers, the number of medical personal exposed to occupational carcinogens is unknown. That all does not show the actual situation in our country and does not allow setting priorities in cancer prevention among medical workers.
RESEARCH ARTICLES
Background. It is generally accepted that crosstalk between the growth factor receptor and ER pathways implicated in tamoxifen resistance. The aim of the study was to examine the relationship between mRNA level, protein expression and gene polymorphism of the EGFR/PI3K/AKT signaling components with tamoxifen efficacy in patients with estrogen-dependent breast cancer. Materials and methods. The study included 95 breast cancer patients who had received adjuvant tamoxifen, of which 31 patients developed recurrence/metastasis after tamoxifen treatment (tamoxifen resistance group), 64 patients did not develop any diseases progression (tamoxifen sensitive group) during the 5 years of follow-up. Genotypes for ESR1 (rs2077647, rs2228480, rs1801132), EGFR (rs1468727, rs2227983), AKT1 (rs1130233) and PTEN (rs11202592) were analyzed using a TaqMan assay. Using reverse transcription-PCR, the relative expression of mRNA for ESR1, EGFR, AKT1 and PTEN was determined. ERα, EGFR, Akt (pS473) and PTEN expression level was evaluated using immunohistochemistry. Progression-free survival (PFS) was estimated by Kaplan – Meier analysis. Results. The minor allele of ESR1 rs2077647 was more prevalent in tamoxifen sensitive tumors compared to tamoxifen resistant tumors (p = 0.044). We found high AKT1 mRNA expression level in tamoxifen sensitive group compared with tamoxifen resistance patients (7.27 ± 5.29 and 0.02 ± 0.01, respectively, p = 0.014). ESR1 rs2228480 was significantly associated with tamoxifen resistance (p = 0.028). EGFR and Akt (pS473) protein expression level was significantly higher in the tamoxifen resistance group compared to tamoxifen sensitive breast cancer patients (p = 0.006 and 0.037, respectively). Patients carrying mutant genotypes of ESR1 rs2228480 had a poorer progression-free survival than those carrying wild and heterozygous variants (log rank p = 0.043). Positive EGFR tumor expression as well as positive Akt (pS473) expression were significantly associated with shorter PFS (log rank p = 0.014 and 0.048, respectively). Conclusion. Polymorphic sites of the ESR1 gene, AKT1 mRNA expression, EGFR expression level and Akt (pS473) protein expression can be potential molecular markers associated with tumor sensitivity/resistance to tamoxifen treatment.
Background. Ocular melanoma is the most common cancer of adult eye and is represented by two main subtypes of uveal (UM) and conjunctival (CM) melanoma with distinct clinical (frequency, localization, histology) and genomic features. The objective is to compare molecular and genetic characteristics of tumors in patients with melanoma of the eye. Materials and methods. In this study molecular profiling of 78 tumors including 73 UM (choroidea, ciliar body and iris) and 5 СM, was evaluated. DNA was isolated from tumor cells collected by macrodissection of FEPE sections of tumor biopsies using proteinase K. The following genes were studied by Sanger sequencing: GNAQ, GNA11, KIT, BRAF, NRAS. Results. Mutations in GNAQ and GNA11 were found in 81 % (59/73) of UM, in 42 % (31/73) and 38 % (28/73) of cases correspondently. GNAQ mutations were more frequent in primary UM (63 %), while GNA11 mutations dominated in metastatic UM (42 %). There was а correlation between frequency of GNAQ/GNA11 mutations and histologic type of UM. GNAQ mutations were identified in 55 % of spindle cell UM, while GNA11 mutations were more frequent in epithelioid cell UM (42 %). There were no differences in frequency of GNAQ/GNA11 mutations in UM of patients of different age (younger and elder 50 years). There was no statistically difference in UM patient outcome with GNAQ or GNA11 mutations. We also detected 3 UM with KIT mutations and 2 UM with BRAF mutations. There was no big difference in frequency of «driver mutations» in UM of choroidea, ciliar body and iris. Molecular profiling of conjunctival melanoma (CM) resembles that of cutaneous melanoma of skin: in 3 (60 %) CM BRAF V600E was identified and in 1 (20 %) – NRAS Q61K. Conclusion. Genetic analysis reveals wide diversity of melanoma of eye and is important for it characterization and treatment.
Background. Chaperone proteins nucleolin (NCL, or C23) and nucleophosmin (NPM, or B23) regulate key cell functions. The most tumors are characterized by over-expression of these proteins, especially in cell nuclei and on the сell surface, as NCL. Differential expression of NCL/NPM in tumor and normal cells is the basis of selective cytotoxicity of cationic peptides – expected ligands for these proteins. Objective. Analysis of the interactions between nucleolin and some peptides with high nonspecific toxicity for tumor cells. Materials and methods. The interaction of 4 previously characterized cationic peptides with nucleolin dimer was analyzed by pair molecular docking using Maestro 11 program. Results and conclusion. It is shown that these peptides can associate with receptor nucleolin molecules, forming energy-stable complexes. In the active centre of NCL molecule were found, at least, 7 positions of amino acids, which bind to the tested peptides at a high frequency (43–100 %). This indicates the conservative structure of dimer NCL, its stable binding to peptide ligands and the possibility of design the optimal structure of cationic peptides that induce tumor cell death due to competing binding to the target proteins.
Objective of the investigation was to study the infection of ethnic Tatars with the Epstein–Barr virus (EBV) and to analyze the genetic structure of the oncogene of the virus, the latent membrane protein 1 (LMP1), in the virus strains of Tatar origin. Materials and methods. The materials for the study were samples of boucle flushes of 60 students from the Kazan State Medical University who are ethnic Tatars (Tatars no less than in the 3rd generation). Amplified from DNA of boucle flushes the nucleotide sequences of the LMP1 samples translated into DNA amino acid sequences, have undergone classification based on the well-known and widely used in literature the R.H. Edwards et al. classification. Results. The analysis of nucleotide and deductive amino acid sequences of the 41 LMP1 amplicons revealed their homology with only three gene variants from the R.H. Edwards et al. classification (1999): 95.8/A (29.3 %; 12/41), Med– (14.6 %; 6/41) and China1 (7.3 %, 3/41). Such variants of LMP1 as Alaskan, Med+, Chinа2, China3 and NC, were not found. Among the LMP1 samples of Tatar origin in 20 cases (48.8 %), the composition of the mutations found did not allow them to be assigned to any of the oncogene variants listed above. Out of this number, in 7 (17.1 %) cases a mono group of LMP1 samples was found, differing not only from representatives of the Slavs, inhabitants of the European part of Russia, but also from other Kazan samples, and was designated as LMP1-TatK. The remaining 13 samples of LMP1 (31.7 %), not belonging to any of the known classifications, formed the group designated by us as an LMP1 group beside the classification (LMP1BC). Conclusion. Continuation of the study of the molecular-biological and functional properties of LMP1 in TatK and BC groups, which constitute 48.8 % of the number of gene samples studied, and an analysis of the peculiarities of the ethnic Tatar genotype, will probably help to clarify whether certain EBV strains influence morbidity and mortality in Tatar population with malignant neoplasms, which include EBVassociated cases.
Background. There are contradictory data on the detection of human papillomavirus (HPV) in the tumor tissue in endometrial cancer (EС). Objective: to assess HPV infection rates in EC tumor tissues and to establish the relationship between the status of HPV infection and tumor morphological characteristics. Materials and methods. 57 formalin-fixed paraffin-embedded (FFPE) tissue samples of EC patients aged 47–78 years were studied. HPV DNAs were found in 54.4 % of samples. Results and conclusion. We did not reveal an association between the HPV tumor status and age, metastasis or invasion depth. However, there was an interdependence between HPV infection and some morphological characteristics of the tumor: its histological type (adenocarcinomas with squamous cell differentiation were HPV-positive 1.8 times more frequent compared to adenocarcinomas without one; in the first case, tumor tissues were more often infected with HPV 16, and in the second case with HPV 18); tumor grade (in the total cohort and in serous-papillary adenocarcinomas, tumors with higher grades were more often HPV-infected: from 0 to 81.8 % and from 0 to 100 % respectively); disease stage (in the total cohort the percentage of HPV-positive tumors in stage II was 2.4 times and in stage III – 1.6 times higher than in stage I, and stage IA tumors were HPV-positive 2.3 times more often than IB tumors); type of tumor growth (tumors with infiltrative growth type were HPV-positive 1.7 times more often than with exophytic growth, and 2.2 times more often than with mixed growth). The achieved results do not allow us to conclude with confidence that HPV is the main tumor forming factor in EC.
Background. The regulation of the content of mature microRNAs (miRNAs) in different cell compartments – the nucleus (N) and the cytoplasm (C) – makes it possible to control their availability for participation in RNA-mediated interference processes. Structurally different miRNAs, processed from different precursors (pre-miRNA), can form duplexes between molecules containing complementary sequences. The appearance of such duplexes can be considered as one of the mechanisms of miRNA activity regulation in respect to their target mRNAs. Objectives. Analysis of the miRNA distribution between nucleus and cytoplasm depending on the energy of duplex formation. Materials and methods. Data on the content of different miRNAs in the nucleus and cytoplasm in two cell lines of different origin: 5-8F of human nasopharyngeal carcinoma (NPC) and postmitotic neurons of the cerebral cortex of rat – has been used. The miRNA sequences used for analysis were taken from the miRBase database, version 22. Bioinformatic analysis of miRNA sequences for detection of molecules capable of forming miRNA duplexes and determination of their minimal free energy (MFE) of formation was carried out with the help of programs: RegRNA, version 2.0, and RNAup. Results. For the first time, a comparative analysis of the intracellular distribution N/C of different miRNAs depending on the energy of duplex formation was performed. Results of bioinformatic analysis of miRNA sequencing in 5-8F cells of human nasopharyngeal carcinoma showed that miRNAs capable of forming high-energy, i. e. more stable, duplexes, accumulate in the cytoplasm, while miRNAs forming low-energy duplexes have a larger N/C value, i. e. the level of these miRNAs is higher in the nucleus. In addition, we show that N/C distribution of miRNAs capable of forming high-energy duplexes is independent from the presence of certain short motifs, that are supposedly associated with their nuclear localization. Conclusion. The revealed enrichment of the pool of cytoplasmic miRNAs by molecules capable of forming more energetically stable duplexes may represent an additional mechanism of regulating miRNA activity in respect to their target mRNAs due to the sequestration of miRNA duplexes in the cytoplasm preventing miRNA interaction with mRNAs.
ISSN 2413-3787 (Online)