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.

Proteins of the AID/APOBEC family are capable of cytidine deamination in nucleic acids forming uracil. These enzymes are involved in mRNA editing, protection against viruses, the introduction of point mutations into DNA during somatic hypermutation, and antibody isotype switching. Since these deaminases, especially AID, are potent mutagens, their expression, activity, and specificity are regulated by several intra-cellular mechanisms. In this review, we discuss the mechanisms of impaired expression and activation of AID/APOBEC proteins in human tumors and their role in carcinogenesis and tumor progression. Also, the diagnostic and potential therapeutic value of increased expression of AID/APOBEC in different types of tumors is analyzed. We assume that in the case of solid tumors, increased expression of endogenous deaminases can serve as a marker of response to immunotherapy since multiple point mutations in host DNA could lead to amino acid substitutions in tumor proteins and thereby increase the frequency of neoepitopes.

Multiple endocrine neoplasia type 1 (MEN 1) is a rare autosomal dominant disorder caused by mutations in the MEN1 gene, which encodes the menin protein. If a patient has the MEN 1 phenotype in the absence of mutations in the MEN1 gene, the condition is classified as a phenocopy of this syndrome. Although significant progress has been made in understanding the function of menin, its role in the oncogenesis of the endocrine glands is still being elucidated. Due to its key role in physiological and pathological processes, the assessment of the menin expression can provide valuable information.

Cysteine cathepsins (Cts) also known as thiol proteinases belong to the superfamily of cysteine proteinases (EC 3.4.22). Cts are known as lysosomal proteases responsible for the intracellular proteins degradation. All Cts are synthesized as zymogens, activation of which occurs autocatalytically. Their activity is regulated by endogenous inhibitors. Cts can be secreted into the extracellular environment, which is of particular importance in tumor progression. Extracellular Cts not only hydrolyze extracellular matrix (ECM) proteins, but also contribute to ECM remodeling, processing and/or release of cell adhesion molecules, growth factors, cytokines and chemokines. In cancer, the expression and activity of Cts sharply increase both in cell lysosomes and in the intercellular space, which correlates with neoplastic transformation, invasion, metastasis and leads to further tumor progression. It has been shown that Cts expression depends on the cells type, therefore, their role in the tumor development differs depending on their cellular origin. The mechanism of Cts action in cancer is not limited only by their proteolytic action. The Cts influence on signal transduction pathways associated with cancer development, including the pathway involving growth factors, which is mediated through receptors tyrosine kinases (RTK) and various signaling mitogen-activated protein kinases (MAPK), has been proven. In addition, Cts are able to promote the epithelial-mesenchymal transition (EMT) by activating signal transduction pathways such as Wnt, Notch, and the pathway involving TGF-β. So, Ctc perform specific both destructive and regulatory functions, carrying out proteolysis, both inside and outside the cell.

DnA methylation has recently been accepted as the most reliable and effective method of diagnosing central nervous system (CNS) tumors. Healthy organs and tumors of different localizations have their own unique methylation structure. Determination of total tumor DNA methylome is the detection of all methylated nucleotides in a tumor. The "gold standard" for analyzing the methylation state of individual cytosines is bisulfite conversion, in which unmethylated cytosines are converted to uracils and read as thymines, while methylated cytosines are protected from conversion.

The case was analyzed for response to nivolumab (Opdivo) monotherapy in a patient with recurrent skin melanoma (10x6x6 cm) and disease dissemination (with multiple lung metastasis), positive for BRAF mutation that followed upon the local therapy (surgical excision) and 6 cycles of adjuvant chemotherapy (at CVD regimen - cisplatin, vinblastine, dacarbazine). Histological results: melanoma. Immunohystochemical: S 100-positive; Melan A - positive; HMB45 - positive, AE1/AE3 - negative, p53 - positive in most cells, vim - positive, ɑ sma - weak in most cells, Ki67 - positive in 20%, BRAFmut, ECOG performance status 1, LDH - 1320 U/L (N <308 U/L). The effective treatment available for metastatic or unresectable melanoma, Opdivo (nivolumab) was given at a dose of 240 mg every two weeks. Overall, 5 courses were indicated. Local recurrence of melanoma at the site of the primary excision began to resolve after 3 courses of immunotherapy with checkpoint inhibitor (nivolumab) which led to a significant decrease in the size of the cancer. And 5 courses of nivolumab therapy demonstrated complete regression of local recurrence and multiple lung metastases. No locoregional recurrence was found on MRI of the neck area. The patient's condition is now satisfactory. She doesn't feel pain and refuses to take pain relievers, leads an active lifestyle (ECOG 0). Serum level of LDH is within normal limits. Currently, the targeted therapy with low molecular weight selective inhibitors of mutant BRAF (vemurafenib, dabrafenib) and immune checkpoint blockers (nivolumab, pembrolizumab) is generally recommended for unresectable skin melanoma patients bearing BRAF mutations. Despite this dual treatment strategy, the use of even one nivolumab (in monoregimen), showed complete regression of both - the local recurrence and multiple lung metastases in the case of a positive BRAF mutation and substantially improved the survival of inoperable cancer patient.

The authors describe a clinical case of a patient with metastatic basal cell carcinoma and secondary resistance to vismodegib. A SMO G416E mutation of unknown clinical significance was found in the gene encoding the transmembrane receptor protein Smoothened (SMO) protein, which suggests a defect in the Sonic Hedgehog (SH) pathway and may cause tumor resistance to the prescribed drug. Comprehensive genomic profiling and in silico analysis have been used to diagnose the tumor.

Dysregulation of transposable elements plays a key role in human carcinogenesis. Physiological aging in humans is also caused by deregulation of transposons. Moreover, aging is associated with the development of cancer. We presented the results of an analysis of data on the presence of common epigenetic changes during aging and carcinogenesis, associated with changes in the expression of microRNAs derived from transposons. We found that aging is characterized by changes in the expression of 21 specific transposon-derived microRNAs associated with the development of malignant neoplasms. Before us, evidence similar to ours on the relationship between the mechanisms of aging and carcinogenesis at the epigenetic level has not been presented. We hypothesized that one of the key mechanisms of aging is an imbalance in the programmed activation of mobile genetic elements, which is reflected in changes in the body's epigenetic regulation and leads to an increased risk of cancer. Since miRNA precursors can be translated with the formation of functional molecules, peptides used in gerontology can be considered as potential anticancer drugs.

Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR) is a method of choice for quantifying micro RNAs (miRNAs). Typically, RT-qPCR data are normalized to reference genes. While miRNAs are used for diagnosing and subtyping breast cancer, various studies show their deregulation in this condition, thus, undermining miRNAs' utility as a reference. This review examines the expression pattern of miR-16 and suggests normalization approaches for breast cancer. We analyzed the data from selected peer-reviewed studies to calculate the standardized mean difference (SMD) with subsequent Chi-square testing and identified the difference in miR-16 expression between breast cancer patients and healthy controls. With a negative SMD value of-0.56 and Chi-square of 62.62 (p-value = 0.05), the deregulation of miR-16 in breast cancer was confirmed. High variance in the stability value (SV) of miR-16 expression levels confirmed its inappropriateness as a control gene in breast cancer. The combination of miR-16 and miR-425 was confirmed as an accurate endogenous control.

Expression levels of matrix metalloproteinases, in particular MT1-MMP, are elevated in pancreatic cancer (PC) cells, and this is associated with increased tumor proliferation, invasion, and migration. MT1-MMP is considered a promising target for drug therapy of PC, but the use of inhibitors and therapeutic antibodies to MT1-MMP is limited because maximal efficiency is only observed in a narrow time interval, at the early asymptomatic stages of the disease. This problem could be solved by immunization to MPs at the moment of detection of the primary tumor. This therapeutic effect could be provided by specific antibodies that can be re-produced in case of relapses. Here, we selected the optimal mode for immunization of mice with MT1-MMP fragments that allows us to obtain a high titer of specific antibodies in the blood serum. The obtained antiserums effectively inhibited MT1-MMP enzymatic activity, migration of PANC-02 PC cells through the collagen matrix, and activation of the main inducers of epithelial -mesenchymal transition, TGF-β and MMP-2. These results maybe useful in the development of drugs for PC treatment, and the approach we propose might form the basis for design of antitumor drugs with prolonged action.