В настоящее время широкое распространение в клинической практике получили препараты, нацеленные на ингибирование иммунных контрольных точек (ИКТ). Однако для значительной группы больных монотерапия ингибитором ИКТ не является эффективной. Одна из причин этого кроется в сложном механизме взаимодействия между рядом белков, являющихся рецепторами и лигандами разных ИКТ, которые одновременно присутствуют на поверхности клетки. Одно из решений этой проблемы — совместное подавление экспрессии нескольких молекул ИКТ. В настоящее время проходят клинические исследования, в которых тестируются комбинации ингибиторов ИКТ. Некоторые из таких комбинаций одобрены для использования в клинической практике. Также в последнее время активно изучаются сигнальные пути, вовлеченные в формирование иммунного ответа в результате трансдукции сигнала через белки ИКТ. Таргетное воздействие на ключевые молекулы этих путей совместно с ингибированием контрольных точек рассматривается в качестве новой стратегии иммунотерапии. В обзоре рассмотрены перспективные мишени иммунотаргетной терапии — PD-1/PD-L1 и TIM-3/Gal-9. Охарактеризованы сигнальные пути, ассоциированные с молекулами этих ИКТ. Проведена оценка потенциальных подходов, основанных на одновременном воздействии на молекулы PD-1, PD-L1, TIM-3, Gal-9 и их сигнальные пути.

Рак желудка (РЖ) характеризуется агрессивным течением и является одной из ведущих причин смерти от онкологических заболеваний. Стандартные схемы лечения не всегда эффективны при этом заболевании, поэтому разработка новых подходов терапии и поиск предиктивных маркеров представляется актуальной научной задачей. Перспективными терапевтическими мишенями при злокачественных новообразованиях являются иммунные контрольные точки (ИКТ). Для понимания патогенеза и оптимизации терапии активно исследуется вклад ИКТ в процессы опухолевой прогрессии. В данном исследовании на выборке пациентов с микросателлитно стабильным фенотипом опухоли РЖ были изучены уровни экспрессии генов ИКТ и их коэкспрессия с генами, вовлеченными в эпителиально-мезенхимальный переход. Проведена оценка ассоциации экспрессии этих генов с клиническими характеристиками РЖ. Показано, что для низкодифференцированных опухолей характерно понижение экспрессии генов CD276 и PVR (p<0,05). Также обнаружено, что развитие метастазов ассоциировано с повышением уровня экспрессии гена TDO2. В случае неметастатического РЖ была выявлена корреляционная связь между уровнями экспрессии генов CD44 и CD276. В группе метастатического РЖ корреляционная связь уровней экспрессии выявлена между генами ADAM17, PVR, CD276 и генами CD44, SNAI1. Полученные данные дополняют представление о молекулярно-генетических механизмах, регулирующих прогрессию опухоли, и могут внести вклад в разработку новых терапевтических подходов, предполагающих совместное ингибирование генов, коэкспрессия которых является особенностью данной нозологии. Gastric cancer (GC) is an aggressive tumor that is one of the leading causes of death from cancer. Treatment regimens are not often effective for this disease, so the development of new approaches to therapy and the search for predictive markers seems to be an urgent scientific task. Immune checkpoints (ICs) are promising therapeutic targets for malignant neoplasms. To understand the pathogenesis and optimize therapy, the role of ICs in tumor progression is being actively studied. In this study, IC gene expression levels and their co-expression with epithelial-mesenchymal transition-related genes were examined in a sample of patients with a microsatellite stable GC tumor phenotype. The association of the expression of these genes with the clinical characteristics of GC was assessed. It was found that the expression of the CD276 and PVR genes was reduced in low-differentiated tumors (p < 0.05). The development of metastases is associated with an increased level of TDO2 gene expression. In non-metastatic GC, a correlation was found between the expression levels of the CD44 and CD276 genes. In metastatic GC, a correlation of expression levels was found between the ADAM17, PVR, CD276 genes and the CD44, SNAI1 genes. The findings add to the understanding of the molecular genetic mechanisms that regulate tumor progression and may contribute to the development of new therapeutic approaches involving mutual inhibition of genes.

Background. Metastasing and degree of differentiation refer to the main clinical characteristics of malignant tumors. Both listed features need an in-depth study that can lead to an understanding of the mechanisms for the occurrence of certain state of cancer cells.Objective. Studying the processes of metastasis and differentiation of the clear cell renal cell carcinoma (ccRCC) on gene expression.Materials and methods. The levels of expression of ten genes in 65 paired samples were studied (ccRCC tumor tissue and the normal kidney tissue) by the real-time polymerase chain reaction.Results. It is shown that the expression of CA9, NDUFA4L2, VWF, IGFBP3, BHLHE41, ANGPTL4 and EGLN3 genes is associated both with the degree of differentiation of the ccRCC and with the metastasis of this tumor. C1QA expression is connected only with metastasis, but does not participate in the process of differentiation of tumor cells. An ambiguous situation with FN1 and CSF1R gene expression is not essential for ccRCC metastasis processes, but may have a certain value for differentiation of cells of this tumor. Low-differentiated tumors have about five times an increased metastasis frequency during the year relative to highly differentiated tumors (odds ratio 4.94). A low correlation of gene expression in tumors with a low degree of differentiation is revealed, as opposed to their high co-expression during tumor progression by TNM classifications.Conclusion. A significant part of genes substantial for the development of ccRCC is associated with both metastasis and the degree of differentiation of the ccRCC, which is due to the similarity of functional changes that stimulate both of these processes. For low-differentiated tumors the number of genes with correlated expression is less than in high-differentiated tumors. This may be due to disorganization of gene expression.

Рак желудка (РЖ) является одной из существенных причин смертности от онкологических заболеваний. Неблагоприятный прогноз при РЖ в значительной мере связан с метастазированием опухоли. Экспрессия генов и микроРНК может являться источником биомаркеров, сигнализирующих о повышенном риске метастазирования опухоли. Выявление генов, ассоциированных с метастазированием опухоли, и создание прогностической панели микроРНК и генов, является весьма актуальным. Нами исследована экспрессия микроРНК miR-34a и miR -335 и генов FGFR2, VEGFR1 и NRP1 при диссеминированном РЖ в сравнении с не метастазирующими опухолями РЖ. Охарактеризована ассоциация с развитием отдаленного метастазирования, указывающая на их качество как кандидатов в маркеры. Сформированы панели, включающая гены и микроРНК - кандидаты в маркеры прогноза. Проведенный сравнительный анализ панелей позволил выбрать в качестве наиболее эффективной панель, включающую miR335/ VEGFR1 /FGFR2, которая демонстрирует наилучшие показатели как кандидат прогноза метастазирования, особенно по значению отношения шансов ОR = 143 и RR = 7,1. Gastric cancer (GC) is one of the significant causes of mortality from cancer. An unfavorable forecast for GC is largely associated with tumor metastasis. Expression of genes and microRNAs can be a source of biomarkers that signal the increased risk of tumor metastasis. The detection of genes associated with tumor metastasis, and the creation of a candidate prognostic panel of microRNAs and genes is very relevant. We investigated the expression of MIR-34A and MIR -335 microRNA and FGFR2, VEGFR1 and NRP1 genes with disseminated gastric cancer in comparison with non-metastatic GC tumors. Association is characterized with the development of remote metastasis, indicating their quality as candidates for markers. Panels are formed, including genes, and microRNAs - candidates for prognostic markers. A comparative analysis of the panels allowed to be characterized as the most efficient panel, including MIR335/VEGFR1/FGFR2, which demonstrates the best indicators as a candidate for the metastasis prediction panel, especially the value of the ratio of the chance of OR = 143 and RR = 7.1.

An association was found between reduced expression of miR-34a, miR-146a with both metastasis to regional lymph nodes (relative risk RR=10.50 and RR=5.25, respectively) and the development of distant metastases (RR=9.50 and RR=4, 40, respectively) in gastric cancer. They are excellent classifiers: AUC>0.9 for both miRNAs. The association of miR-335 expression with metastasis to the lymph nodes is much weaker, but it is also a good classifier for identifying a group with distant metastasis (RR=5.90). A correlation was found between the expression of miR-34a and miR-146a during metastasis, which is absent in non-metastatic tumors. Thus, miR-34a, miR-146a, and miR-335 miRNAs can be proposed as candidates for biomarkers of the risk of gastric cancer metastasis.

The expression levels of miR-146a and the target gene of this miRNA, NF-kB, in gastric cancer (GC) samples at different stages of metastasis development were studied. The expression of miR-146a in the samples of the GC decreased with the involvement of regional lymph nodes in the metastatic process. A negative correlation was found between the expression level of miR-146a and the number of regional lymph nodes damage (Spearman’s correlation coefficient (R) was R = - 0.61; p 0.005). On the contrary, NF-κB gene expression increased with lymph node metastases. An inverse correlation was found between miR-146a and NF-κB (R = -0.76; p 0.03). The first detected negative correlation of expression between miR-146a and NF-κB may indicate activation of the NF-κB signaling pathway in GC cells with a decrease in miR-146a expression. Apparently, this signaling pathway is important in the development of metastases of gastric cancer.

Были изучены уровни экспрессии miR-146а и гена-мишени этой микроРНК - NF-kB в образцах рака желудка (РЖ) на разных этапах развития метастазов. Экспрессия miR-146а в образцах РЖ понижалась по мере вовлечения регионарных лимфоузлов в метастатический процесс. Была обнаружена отрицательная корреляция уровня экспрессии miR-146а со степенью поражения регионарных лимфоузлов (коэффициент корреляции по Спирмену (R) составил R = - 0,61; p=0,005). Напротив, экспрессия NF-kB повышалась при поражении лимфоузлов метастазами. Обнаружена обратная корреляция между miR-146a и NF-kB (R = -0,76; p=0,03). Впервые обнаруженная отрицательная корреляция экспрессии между miR-146a и NF-kB может указывать на активацию сигнального пути NF-kB в клетках РЖ при снижении экспрессии miR-146a. Видимо, этот сигнальный путь имеет значение при развитии метастазов РЖ. The expression levels of miR-146a and the target gene of this miRNA, NF-kB, in gastric cancer (GC) samples at different stages of metastasis development were studied. The expression of miR-146a in the samples of the GC decreased with the involvement of regional lymph nodes in the metastatic process. A negative correlation was found between the expression level of miR-146a and the number of regional lymph nodes damage (Spearman’s correlation coefficient (R) was R = - 0.61; p 0.005). On the contrary, NF-κB gene expression increased with lymph node metastases. An inverse correlation was found between miR-146a and NF-κB (R = -0.76; p 0.03). The first detected negative correlation of expression between miR-146a and NF-κB may indicate activation of the NF-κB signaling pathway in GC cells with a decrease in miR-146a expression. Apparently, this signaling pathway is important in the development of metastases of gastric cancer.

Desmoid-type fibromatosis (DF) is a rare mesenchymal tumor occurring in only 2 to 4 people per 1,000,000 population a year. Desmoid tumors are either seen sporadically or in individuals with familial adenomatous polyposis (FAP). The etiology of sporadic DF is uncertain. The aim of this study was to estimate the potential significance of germline mutations in the APC gene in patients with sporadic DF. APC exons were amplified, studied using conformation sensitive gel electrophoresis and then Sanger-sequenced. The obtained data were processed in Statistica 10. Mutations were detected in 6 (12%) of 51 participants with sporadic DF. Those 6 patients shared a typical DF phenotype characterized by early age of onset (5.8 years on average, in contrast to the patients without APC mutations, who developed DF at 19 years of age; p = 0.02), severe clinical course, multifocal localization on the trunk, and poor prognosis. All of the detected APC mutations were localized to the 3'-end of the gene. For the purpose of comparison, we analyzed a sample of 12 patients with FAP-associated DF. Of those patients, 6 carried mutations in the APC gene. In the analyzed sample, the patients with FAP and the mutant APC gene developed DF at older age (35 years) than the patients with sporadic DF (p = 0.004) and their tumors were not multifocal. This means that sporadic and FAP-associated desmoids have different phenotypes in patients with APC mutations. Patients with sporadic tumors have mutations at the 3'-end of the APC gene more often than individuals with FAP-associated DF. To our knowledge, this is the first study to characterize the subtype of sporadic desmoid fibromatosis phenotypically determined by germline mutations in the APC gene.

Objective of the study . Identification of genes, the expression of which is associated with the metastasis of gastric cancer tumor. Materials and methods . Quantitative real-time PCR on paired tumor – normal samples. Results . An association with the metastasis of the VEGFR1, FGFR2 and NRP-1 gene expression is shown. The odds ratio (OR) was the highest for the FGFR2 gene: OR 175.00; 95 % CI 8.972–3413.271; for the VEGFR1 gene, OR 4.622, 95 % CI 1.240–17.227, for NRP1 – OR 2.667; 95 % CI 0.597–11.915. When assessing the jointly elevated expression of VEGFR1 and NRP1 genes, OR 5,778; 95 % CI 1.393–23.909; p = 0.0147. The frequency of increased expression of FGFR2 was 5 % in case of metastasis, while in the case of localized GC it reached 53 %. Conclusion. The target drug against FGFR2, which is being developed, is likely to have a limited 5–10 % frequency of effective action in metastatic GC. Its use in the early stages of GC can help prevent the transition of the tumor to the metastatic stage. The possible interact tion of VEGFR1 and NRP1 will result in a small contribution to the metastasis of GC as compared to the effect of VEGFR1-only expression.

Десмоидные фибромы (ДФ) — редкие мезенхимальные опухоли с частотой возникновения 2–4 случая на 1 млн человек в год. Они могут возникать как спорадически, так и в ассоциации с семейным аденоматозным полипозом (САП). Природа возникновения спорадических ДФ ранее не была выяснена. Целью исследования было определить возможную значимость герминальных мутаций гена АРС у пациентов со спорадическими ДФ. Экзоны гена АРС амплифицировали и исследовали с помощью конформационно-чувствительного электрофореза в полиакриламидном геле и последующего секвенирования по Сэнгеру. Статистическую обработку результатов проводили с помощью пакета программ «Statistica 10». При исследовании 51 случая спорадических ДФ мутации выявлены у 6 человек (12%). Пациенты с выявленными мутациями имели характерный фенотип: раннюю манифестацию (в среднем в 5,8 года, в то время как у пациентов без мутаций — в 19 лет (р = 0,02)); тяжелое течение заболевания; мультифокальный рост ДФ, локализованных на туловище, и неблагоприятный прогноз. Все выявленные мутации были обнаружены в области 3'-конца гена APC. Для сравнения со спорадическими были исследованы ДФ, связанные с САП (12 человек), мутации выявлены у 6 из них. При мутации в гене АРС у пациентов с САП не было выявлено случаев множественных ДФ, фибромы у пациентов с САП развивались позже (35 лет), чем у пациентов со спорадическими ДФ (p = 0,004). Следовательно, при мутациях в одном и том же гене фенотипы спорадических и ДФ, связанных с САП, различны. Для спорадического ДФ характерно более частое расположение мутаций на 3'-конце гена АРС по сравнению с ДФ при САП. Таким образом, впервые среди спорадических ДФ охарактеризован подтип с фенотипическими особенностями, обусловленными герминальными мутациями в гене APC.

This review is designed to discuss possibilities for the treatment of advanced gastric cancer with reference to the prognostic and predictive value of molecular-biological parameters and the influence of hereditary predisposition to the development of neoplastic process. The data on modern pharmacotherapy of this disease based on the knowledge of molecular-biological parameters are presented including the following markers: HER2/neu, VGFR, c-met, TUBB3, CDH-1, BRCA-1, EGFR, TGF-ß, p53, Ki67 and PCNA. It is emphasized that the role of molecular-biological parameters associated with advanced gastric cancer is ambiguous. The prognostic and predictive significance of some of the markers is confirmed while that of others remains to be elucidated and requires further research.

Objective is the investigation of messenger RNA quantitative expression profiles of potential target genes among disseminated gastric cancer cases. Materials and methods. Quantitative real-time polymerase chain reaction on paired tumor-normal samples. Results. The most frequently (25-41 % of cases) an increased level of messenger RNA in the tumor with respect to normal tissue was observed for the genes of TGF-ß (transforming growth factor ß), NRP-1 (neuropiline 1) and VEGF (vascular endothelial growth factor) family genes. For the first time a correlation between the expression levels of the three genes: NRP-1, TGF-ß and VEGFR-2, and the inverse correlation of the levels of VEGF and bFGF gene expression were found. Conclusion. The revealed correlation between the expression of TGF-ß, NRP-1 and VEGFR-2 genes is apparently due to the interaction of NRP-1 with the products of two other genes and may be associated with a high metastatic potential of the progressing tumor in disseminated gastric cancer. The observed inverse correlation of the VEGF-A and bFGF gene expression may indicate the stimulation of angiogenesis in the tumor with reduced activity of the VEGF pathway by activating the bFGF signaling pathway. The results obtained should be taken into account under targeted therapy.

Breast cancer (BC) is the second most common type of cancer worldwide and affects 1 in 8 women over the course of their lifetime. A personalized approach to treating BC can substantially increase efficiency and consequently maintain the active life of many people. This encourages investigators and physicians to better understand tumor biology in order to make a correct diagnosis, to determine recurrence risk, and to choose adequate therapy. This paper discusses the bases for the molecular classification of BC into its expression subtypes, as well as current prognostic kits that assist oncologists in classifying the subtypes of cancer and in predicting the development of the disease. The existing test systems are not universal, each of them is applicable only to a limited group of patients, but they totally cover a considerable number of cases. The tumor gene mutations in BC, which have been characterized by up-to-date methods, can serve as predictive markers for the efficiency of targeted therapy.

About 3% of cases of gastric cancer (GC) cases are due to hereditary predisposition. Molecular causes of inherited predisposition to diffuse GC among Russian patients have not been studied. In the present work there was performed the molecular genetics study in 9 probands with signet-ring cell GC. Search of hereditary mutations was conducted in a suppressor gene of diffuse GC - the gene CDH1. We have discovered a new hereditary mutation (c.1005delA) and one rare variant (s.2253C> T). Frequency of hereditary mutations in sample of patients Russian was 1/9 (11,1%).

The spectrum of mutations in the APC gene in familial adenomatous polyposis was detected in a sampling from the Russian population. Fifteen new mutations were found. Deletions associated with the loss of only 1 or 2 nucleotides (89% cases) prevailed among new (unique) mutations, while all known deletions were caused by the loss of 4 or 5 nucleotides. The detected differences in the deletion characteristics between unique and repeated mutations in the APC gene were typical of samples of patients from a number of populations. Samplings from different populations were heterogeneous by this sign. The incidence of 1–2-nucleotide deletions among unique and repeated deletions in the APC gene in patient samplings from different countries were in negative correlation.