High carcinogenic-risk human papillomaviruses (hrHPVs) are recognized as etiological agents of cervical cancer. Constant expression of the viral oncoproteins, E6 and E7, is required for maintenance of the malignant phenotype of tumor cells. The exact mechanism of regulation of viral oncogenes expression in tumor cells is not fully elucidated.

The analysis of literature revealed that men experience uveal melanoma (UM) more frequently and with worse prognosis. There are also descriptions of an aggressive course of UM in pregnant women. These facts prompted researchers to analyze the effect of sex hormones and pregnancy on the development and progression of UM. Many years of international experience have refuted the presence of a reliable difference between 5-year survival and 5-year survival without metastases between non-pregnant women with UM and pregnant women with UM. That data is regarded as level 3 evidence. The experts have concluded that UM is not a contraindication to current or future pregnancy, and exogenous hormones (oral contraceptives or hormone replacement therapy) do not affect the incidence and prognosis of UM. Publications provide evidence of expression of the receptors of certain sex hormones (ER, ERRα, LH and LHRH) in primary UM, as well as overexpression of the ESR1 and ESR2 genes in UM with poor predictive characteristics. Overall AR mRNA expression in UM was low, but it was higher in epithelial UMs. The fact of expression of estrogen receptors in UM gives grounds to experiment with them as a target for therapy.

Embryonal tumor with multilayered rosettes (ETMR) is a rare and highly malignant brain tumor that develops in children younger 4 years old. This neoplasm is characterized by extremely aggressive course, low sensitivity to chemotherapy and radiotherapy. Thanks to the progress of pathologists, diagnosis of ETMR is now available using immunohistochemical examination with LIN28A and SALL4 antibodies. Moreover, detection of microRNA amplification in the 19q13.42 locus by fluorescent hybridization in situ allows an unmistakable diagnosis. The authors describe clinical course and treatment outcome in a 2-year-old patient with a giant tumor of the right parietotemporal region. Postoperative histological examination verified ETMR. Despite adjuvant treatment, we observed fast progression of disease and unfavorable outcome after 5 months. Case report is supplemented by literature review.

Glioblastoma (GB) is one of the most aggressive primary brain tumors. Analysis of molecular genetic factors affecting prognosis in patients with GB is an important direction of fundamental and clinical researches. There are literature data on the effect of TERT gene mutations, MGMT methylation and IDH1/2 status on overall survival in patients with GB.

The article lists the main inducers of cholangiocarcinogenesis. The main inflammatory mediators (IL-6, nitric oxide, COX2) have been considered. Data on the study of gene mutations in cholangiocarcinomas are presented. The spectrum of genetic mutations depends on the biliary cancer origin (FGFR2 with intrahepatic cholangiocarcinoma, PRKACA, PRKACB with extrahepatic cholangiocarcinoma). Mutations in the KRAS, TP53, ARIAD1A genes are common in extrahepatic bile duct cancer. The role of epigenetic changes such as DNA hypermethylation, histone modifications, chromatin remodeling, as well as disturbances in miRNA expression is presented. A number of epigenetic features, such as the presence of a TP53 mutations with hypermethylation of p14ARF, DAPK, and/or ASC, correlate with a more aggressive course of the disease. The role of the SOX17 gene in the development of drug resistance is highlighted. The study of the molecular genetic features of extrahepatic bile duct cancer can help to better understand the pathogenesis of this type of tumor, to establish new prognostic and diagnostic markers of the disease.

The review is focused on a relatively new research method in oncology - DNA methylation. Starting from the methylation of individual genes, the method is gradually expanding and becoming routine for studying the global structure of DNA methylation (methylome) in tumors of various localizations. For some tumors (carcinomas of the mammary and thyroid glands), the study of the global structure of DNA methylation is just beginning, while methylation classifiers have been proposed and successfully used in the Russian Federation for brain tumours and sarcomas. This article compares the fifth edition of the WHO Classification of tumours of the Central Neurvous System and the methylation brain classifier.

Here we report three patients with rare primary intracranial sarcomas, two of them were CIC-sarcomas and one was a DICER1-sarcoma. Tumors were examined using DNA methylation. It is important to study of CIC fusions and DICER1 mutations in malignant brain tumors.

Super-enhancer consists of a large cluster of transcription enhancers that regulates the expression of genes playing an important role in the growth and development of malignant tumors. Recently, several attempts for the identification of super-enhancers have been made, but their functional role in tumor cells remains unclear. This paper aims at elucidating the functional properties of KLF6 super-enhancer related to the growth regulation of HepG2 cells, in relation to transcription factors (TFs). First, some TFs specifying KLF6 super enhancer were identified using CRISPR/Cas9 system and siRNA. Then, their effects on the expression of the target gene KLF6 were assessed. Last, their influence on the proliferation of tumor cells was considered using the MTT method. The study shows that the active enhancers of KLF6 super-enhancer recruit GATA2 and SOX10 TFs to control the expression of the target gene, KLF6. Our findings suggest that the activity of KLF6 super-enhancer is regulated by two TFs (GATA2 and SOX10), and its targeting may be a potential therapeutic strategy for the liver cancer therapy.

The article presents the main molecular mechanisms of the pathogenesis of renal cell carcinoma. The molecular pathways that determine the development of histological variants of renal cell carcinoma and the role of stem cells markers in the carcinogenesis of these tumors are considered.

Difficulties in the diagnosis and differential diagnosis of melanoma in the work of a pathologist include not only conflicting structural and morphological features, but also the insufficient effectiveness of biochemical and some molecular markers in immunohistochemical studies. The review presents modern alternative methods for diagnosing malignant tumors based on the assessment of gene expression, the performance, objectivity and reliability of the determination of which may in the future have clinical application as an addition to histopathological methods in the diagnosis and differential diagnosis of various malignant neoplasms, including melanocytic neoplasms, which is changing the paradigm of routine medical practice, introducing diagnostic tests that carry molecular information into it.

Over the past decade, next generation sequencing (NGS) has become the standard method in research of cancer genomics; currently NGS is entering a new stage - direct usage in clinical oncology to improve diagnostics and establish personalized tumor treatments. NGS allows to read the genome and it is successfully applied to detect mutations and other somatic changes (translocations, inversions, insertions and deletions, copy number variants) leading to the development of a tumor. With a focus on transcriptome sequencing allows to clearly identify differences in gene expression, improve the classification of tumors and detect somatic chimeras. All these possibilities are especially relevant for pediatric neurooncology filed in view of the existing limitations in treatment and the need for the most accurate identification of the key factors of tumor development. In this article, we describe sequencing technology basis, its application on brain tumor materials to improve diagnostics, and other relevant possibilities that can be considered for direct usage in medicine.

The case of dichorionic twin pregnancy is described, with a fused placenta, one part of which is represented by a tissue of partial hydatidiform mole (PHM) with signs of regression, the second part is a placenta of a common structure with a normal development of the second twin. The delivery took place at the term of 38 weeks with a live healthy girl weighing 3250 g. A single placental disc consisted of two fused placentas with a clear boundary between them. The placenta of a live-born girl was mature, with focal chorangiosis, the second part of the disc was represented by the PHM tissue with avascular giant bizarre villi, some of them with central cisterns, with stromal fibrosis, low proliferative activity of the villous trophoblast and a significant narrowing of the intervillous space. A genetic study was carried out on the material of paraffin blocks from two parts of the placental disc containing the tissue of the villous chorion, and the blood of the parents. Comparative analysis of DNA isolated from the paraffin block of PHM with the DNA of the parents revealed the presence of diandric dispermic triploidy. No chromosomal pathology was found in the placenta of a living girl. For hydatidiform mole in the case of multiple pregnancy, an increase in the volume of the affected placenta is characteristic compared to the normal placenta of the twin. In our observation, the presence in the placenta with PHM signs characteristic of placentas with antenatal fetal death, stromal fibrosis of the villi and low proliferative activity of the trophoblast suggests a regression of PHM.

Anaplastic pleomorphic xanthoastrocytoma is a rare tumor. There are still no objective data on the incidence of its diagnosis.

The transcription factor p73 is a member of the p53 tumor suppressor gene family and one of the key regulators of apoptosis. TP73 gene encodes two protein isoforms classes with diverse functions, TAp73 and DNp73, and TAp73 expression in tumor tissues is altered. Unlike the TP53 gene, TP73 is not mutated in cancers. Here, we sought to explore the expression of p73 isoforms across eight major cancer types using the publicly available data deposited at the GDC data portal and the TSVdb database. Our results showed that TAp73α is overexpressed in breast invasive carcinoma, stomach adenocarcinoma, lung squamous cell carcinoma, colon adenocarcinoma, and esophageal carcinoma tumors, whereas the expression of DNp73 isoforms is downregulated in breast invasive carcinoma (DNp73α,β,γ), Prostate Adenocarcinoma (DNp73β), Lung Adenocarcinoma (DNp73α), Lung Squamous Cell Carcinoma (DNp73α) tumors. In summary, this study revealed that TAp73α has higher expression than the DNp73 isoforms in several cancer types.

The review presents information on the role of hepatitis B virus (Hepadnaviridae: Orthohepadnavirus: Hepatitis B virus) (HBV) X gene and the protein it encodes (X protein) in the pathogenesis of viral hepatitis B. The evolution of HBV from primordial to the modern version of hepadnaviruses (Hepadnaviridae), is outlined as a process that began about 407 million years ago and continues to the present. The results of scientific works of foreign researchers on the variety of the influence of X protein on the infectious process and its role in the mechanisms of carcinogenesis are summarized. The differences in the effect of the X protein on the course of the disease in patients of different ethnic groups with regard to HBV genotypes are described. The significance of determining the genetic variability of X gene as a fundamental characteristic of the virus that has significance for the assessment of risks of hepatocellular carcinoma (HCC) spread among the population of the Russian Federation is discussed.

Multiple endocrine neoplasia type 1 syndrome (MEN1) is a rare inherited disorder that can include combinations of more than 20 endocrine and non-endocrine tumors. Unfortunately, none of the described MEN1 mutations has been associated with a peculiar clinical phenotype, even within members of the same family, thus a genotype-to-phenotype correlation does not exist. MEN1 syndrome is the most common cause of hereditary primary hyperparathyroidism (PHPT), the disease penetrance of which exceeds 50% by the age of 20 and reaches 95% by the age of 40. At the same time, PHPT with hyperplasia or adenomas of the parathyroid glands (PTG) is the most distinctive manifestation of the MEN1 syndrome. One of the main symptoms of PHPT, both in sporadic and hereditary forms of the disease, is bone damage. At the time of diagnosis in PHPT/MEN1, the bone mineral density is generally lower in comparison with the sporadic form of PHPT. This may be due to excessive secretion of parathyroid hormone during the period of peak bone mass, concomitant components of the syndrome, extended surgical treatment, and the direct effect of a mutation in the menin gene on bone remodeling. This clinical case describes a young patient with severe bone complications of PHPT and uncertain rare MEN1 mutation. PHPT was diagnosed five years later from the first onset of bone complications and repeated orthopedic operations. There was the «hungry bones» syndrome after successful surgery of PHPT, which was managed with vitamin D and calcium carbonate supplementation and there is a positive dynamic in increased bone mineral density in the main skeleton after 6 months.

The widespread introduction of genetic testing in recent years has made it possible to determine that more than a third of cases of pheochromocytomas and paragangliomas (PPPGs) are caused by germline mutations. Despite the variety of catecholamine-producing tumors manifestations, there is a sufficient number of clinical and laboratory landmarks that suggest a hereditary genesis of the disease and even a specific syndrome. These include a family history, age of patient, presence of concomitant conditions, and symptoms of the disease. Considering that each of the mutations is associated with certain diseases that often determine tactics of treatment and examination of a patient, e.g. high risk of various malignancies. Awareness of the practitioner on the peculiarities of the course of family forms of PPPGs will allow improving the tactics of managing these patients.The article provides up-to-date information on the prevalence of hereditary PPPGs. The modern views on the pathogenesis of the disease induced by different mutations are presented. The main hereditary syndromes associated with PPPGs are described, including multiple endocrine neoplasia syndrome type 2A and 2B, type 1 neurofibromatosis, von Hippel-Lindau syndrome, hereditary paraganglioma syndrome, as well as clinical and laboratory features of the tumor in these conditions. The main positions on the necessity of genetic screening in patients with PPPGs are given.

Using a model of the human SK-Mel-147 melanoma cell line, it was shown that blocking the expression of integrin α3β1 by transduction of cells with α3-specific shRNA did not affect their proliferation, but sharply increased the proportion of SA-β-Gal-positive cells, a phenotypic feature of cell senescence. These findings were accompanied by a significant increase in the activity of the Akt and mTOR protein kinases and the expression of p53 and p21 oncosupressors. Pharmacological inhibition of mTORC1 reduced the number SA-β-Gal-positive cells in the SK-Mel-147 cell population depleted of α3β1. Based on our recent data on a non-canonical function of Akt isomers in the regulation of SK-Mel-147 cell senescence caused by deficiency of α2β1 receptor, we investigated the role of Akt isomers in senescence induced by the α3β1 knockdown. It appeared that in the cell population with downregulated α3β1, inhibition of Akt1 reduced the number SA-β-Gal positive cells to the level of control cell population, while inhibition of Akt2 had no visible effect. Our results demonstrate that the laminin-specific integrin α3β1, like the collagen-specific receptor α2β1, is involved in tumor cell protection from senescence, and senescence induced by α3β1 depletion, like that caused by α2β1 deficiency, is based on a signaling mechanism employing a non-canonical function of the Akt1 isoform.

The novel molecular subtype of breast cancer (BC), named "claudin-low", was described in 2007. It was characterized by the consistently low expression of genes involved in the formation of epithelial tight junctions in combination with the high activation of genes associated with the epithelial-to-mesenchymal transition, as well as tumor stem cell markers. The similar claudin- low subtype was later identified at the transcriptional level in bladder cancer, gastric cancer, and serous ovarian cancer. However, only in relation to BC, attempts were made to create a surrogate panel for immunohistochemical identification of this subtype in a manner like the intrinsic molecular BC subtypes identified using three main markers, such as ER, PR, and HER-2. At the same time, the ambiguity in the expression of claudins among the subtypes of BC, which is defined by various authors at the immunohistochemical level, as well as the absence of both the confirmed set of immunohistochemical criteria and a unified approach to their assessment, complicate these efforts. The purpose of the review is to show that the immunohistochemical identification of claudin-low subtype of BC is a separate problem that has significant limitations, needs standardization and has not yet reached diagnostic value.

Alpha fetoprotein (AFP) is a growth factor and a signaling molecule that promotes the development of HCC. However, the mechanism of the awakening of AFP in course of HCC progression remains unclear. We have studied the structure of AFP 5'-flanking regulatory sequence using dual-luciferase reporter vectors with fragments of this region. Reporter constructs were transfected into HepG2 and PLC hepatoma cell lines. The AFP 5'-flanking regulatory sequence between -1871 and -1004 bp was promoting gene transcription, while the effects of the sequence between -1004 and -667 bp were small. The fragment located between positions -667 and -448 bp inhibited the transcriptional activity of the AFP gene, while the fragment located between -448 and -287 bp promoted expression of AFP. The effects of the adjacent promoter sequence were small. A variety of transcription factor binding sites were mapped.