The most common somatic mutations in solid tumors affect the TP53 gene, leading to the formation of the tumor-specific p53 antigen through overexpression of the wild-type antigen (WT-p53) or the generation of mutant-specific neoepitopes (MUT-p53). Thus, the p53 protein is a promising target for immunotherapy. This article summarizes clinical and immunological data on p53-targeting vaccine strategies. Vaccination against WT-p53 is shown to reproducibly induce p53-specific T-cell responses and has a favorable safety profile; however, its clinical efficacy as a monotherapy is limited. Key challenges include central immune tolerance to WT-p53 epitopes, low density of p53 peptide-HLA complexes on the tumor cell surface, an immunosuppressive tumor microenvironment, and HLA (HLA – human leukocyte antigens) heterogeneity. For mutant p53, specific immunogenic epitopes have been validated, yet phase II clinical trials of vaccines targeting frequent p53 mutations are still lacking. Future prospects for enhancing the efficacy of p53-targeted vaccines lie in combination strategies (e.g., with immune checkpoint inhibitors, adjuvants), precise patient stratification, and for mutant p53, the application of TCR-based (TCR – T-cell receptor) technologies and the development of personalized neoantigen selection platforms.
Introduction. Gastric cancer is an aggressive malignant tumor of the gastrointestinal tract. Its onset and development are associated with genetic and external factors. Abnormalities in DNA repair genes, for example ERCC1 and ERCC2, can play a role in the development of this disease. Aim. To determine prognostic significance of ERCC1 (rs11615, rs3212986) and ERCC2 (rs13181) gene polymorphisms in the development of gastric cancer in the Kyrgyz population. Materials and methods. The study included 123 patients with malignant tumors of the stomach and 138 healthy individuals belonging to the Kyrgyz ethnic group. Genotyping was performed using allele-specific polymerase chain reaction. Statistical analysis included Fisher’s exact test and calculation of odds ratio (OR) for evaluation of associations between genotypes and clinical parameters. Genotyping results, histological and morphological tumor structures, patient age, tumor growth and location were compared using Fisher’s exact test. OR was determined through cross-tabulation. Results. Statistically significant association of CC genotype of the ERCC1 (rs3212986) polymorphic locus with patient age (41–50 and 61–70 years) was found. Genotypes TG and TT of the ERCC2 (rs13181) gene were associated with poorly differentiated adenocarcinoma. Additionally, it was shown that CA genotype and A allele of the rs3212986 (ERCC1) polymorphism can play a protective role decreasing the likelihood of gastric cancer development in the Kyrgyz population (OR 0.472; 95 % confidence interval 0.287–0.785 and OR 0.676; 95 % confidence interval 0.464–0.991 for CC genotype and allele A, respectively) (р = 0.046). Conclusion. Polymorphisms of the ERCC1 and ERCC2 genes can be associated with the risk of gastric cancer development in the Kyrgyz population. These data show the necessity of further studies investigating the role of these genes in gastric cancer and development of strategies for its prevention and treatment.
For various types of solid tumors, bones are the most common location of metastases. Bone is a dynamic organ capable of simultaneously performing multiple auxiliary functions in the body. Osteoblasts and osteoclasts and their changes play a significant role in bone remodeling. Aim. To summarize current data on bone metastases for better understanding of biological nature of oncogenesis. The article analyzes recent scientific publications containing information on molecular mechanisms of metastasis into the bone from the National Center for Biotechnology Information (NCBI), eLibrary and Google Scholar databases, as well as characterizes bone cells and their role in oncogenesis. Knowledge and deep understanding of bone metastasis in various solid tumors are necessary for development of accurate diagnostic methods and effective modern treatment of patients with bone metastases. Currently, the mechanisms of cancer metastasis and interactions between metastatic cancer cells and bone microenvironment are not completely understood. Epigenetic changes associated with differentiation of osteoblasts and osteoclasts and cell signal transduction play a large role in bone remodeling in various malignant neoplasms. Increased bone resorption is caused by disbalance between osteoblasts and osteoclasts. Osteoclast activity leads to release of growth factors from the bone matrix necessary for tumor cell multiplication in the bone.
Anti-cluster-of-differentiation (anti-CD) antibody microarray is an attractive multiplex analogue to leukocyte immunocytochemistry for surface markers. The transparent plastic microarray support permits to sort leukocytes by their surface lineage-specific markers making them available for subsequent high-resolution morphology examination. The combined data on the pathologic cells’ immunophenotype, morphology and cytochemistry from the microarray is sufficient to suggest preliminary diagnosis in many leukemia types. However, in some cases additional staining for internal markers is required, i.e. in T cell acute leukemia the T cell origin of the blasts can only be proved by the presence of cytoplasmic CD3 (cytCD3). Here we describe a new protocol of immunocytochemical detection of internal proteins in mononuclear cells captured by mouse anti-CD antibodies on the microarray surface. The protocol uses primary mouse FITC-conjugated (FITC – fluorescein isothiocyanate) antibodies against the target, secondary anti-FITC antibodies conjugated with alkaline phosphatase and colorimetric alkaline phosphatase substrate, BCIP/NBT. We show on normal leukocytes and leukemic cell lines that the protocol is sensitive and specific. The percentages of cytCD3-positive cells determined by this method in bone marrow aspirates of two patients with T cell acute lymphoblastic leukemia are in excellent agreement with flow cytometry results. This method expands the diagnostic capabilities of anti-CD antibody microarray.
Introduction. In 20–25 % of cases of patients with hereditary forms of breast cancer (BC), pathogenic variants of the BRCA1 and BRCA2 genes predisposing to BC and ovarian cancer can be identified. Based on the results of previous Russian studies, a simple and inexpensive testing system using real-time polymerase chain reaction consisting of the 8 most frequently identified variants (mutations) in the BRCA1 and BRCA2 genes was developed. The use of targeted panels for high-throughput sequencing and whole genome sequencing for diagnosis of hereditary BC led to identification of a number of genes with pathological variants causing this pathology in patients and their relatives. Aim. To evaluate the profile and frequency of pathological variants in genes associated with tumor development in Russian patients with BC. Materials and methods. Analysis of the results of whole genome sequencing of samples from 1514 patients with BC and 5163 individuals without oncological diseases (control group) was performed. Results. A spectrum of mutations in the BRCA1 and BRCA2 genes, as well as pathogenic variants in other genes, were identified. Based on the results of whole genome sequencing a new panel was developed consisting of 10 most common mutations in the BRCA1, BRCA2, АТМ and PALB2 genes. Additionally, significant associations between pathogenic variants in the ATM gene with estrogen-positive luminal BC (р = 0.034) and pathogenic variants in the BRCA1 gene with triple negative BC (p 0.001) were found. Conclusion. In accordance with the obtained data, the new panel of the most common pathogenic variants includes BRCA1 (rs28897672, rs80357522, rs80357906, rs41293455, rs80358094), BRCA2 (rs28897756, rs80359604), АТМ (rs587782652) and PALB2 (rs180177143, rs515726123). Implementation of the new extended panel for identification of frequent mutations in Russian patients with BC in clinical practice will allow to identify up to 7.7 % of germline variants in a random sample.
