Advances in Molecular Oncology

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.

Epstein–Barr virus (EBV) is a human herpesvirus type 4, which is carried by the majority of the world’s population. Its etiologic role in the development of various lymphomas, nasopharyngeal cancer, gastric cancer, and other malignancies has been proven. The mechanisms and participants of EBV-associated oncogenesis are actively studied. This review describes the molecular genetic diversity of EBV associated with the development of cancer. A literature review revealed that EBV is characterized by high structural and functional diversity of nucleotide and amino acid sequences. Based on polymorphism of EBV genes EBNA-1, EBNA-2, EBNA-LP, EBER, BZLF1, LMP-2A and LMP-1, various mutations, types, and variants, associated with malignant transformation and the development of various cancer types were identified.

Aim. To summarize and analyze literature data devoted to the study of the genetic diversity of EBV for the prospective development of molecular biological research methodology in clinical practice, as well as the development of diagnostic tools, specific prevention and therapy of EBV-associated oncological diseases based on the products of the viral genome.

Introduction. The development of chemoresistance is a key factor limiting the efficacy of ovarian cancer therapy. Although high MUC16 gene expression levels in tumors are a known adverse prognostic factor, its role in predicting response to specific chemotherapeutic agents remains understudied. This led to the hypothesis that the adverse prognostic value of MUC16 expression levels may be mediated by its contribution to the development of chemoresistance.

Aim. To evaluate the association between MUC16 gene expression levels and in vitro resistance to standard chemotherapy agents, including carboplatin, cisplatin, and paclitaxel, as well as key clinicopathological characteristics (BRCA1/2 mutation status, platinum sensitivity) and progression-free survival in patients with ovarian carcinoma.

Materials and methods. Tumor samples were obtained from 35 patients with ovarian malignancies, predominantly high-grade serous carcinoma. MUC16 gene expression levels were determined using quantitative real-time polymerase chain reaction. Tumor cell chemoresistance was assessed in vitro in primary cultures using a resazurin metabolic assay, followed by the calculation of the resistance index (Resistance Sensitivity Index, RSI) for each drug. Statistical analysis was performed using Spearman’s rank correlation analysis, the Mann–Whitney U test, and the log-rank test.

Results. High MUC16 gene expression levels were associated with shortened progression-free survival (p = 0.0437). A statistically significant positive correlation was identified between MUC16 gene expression levels and the paclitaxel RSI (R = 0.3614; p = 0.0388). However, no associations were found with the RSI for platinum-based drugs. Furthermore, no relationship was established between MUC16 gene expression levels and BRCA1/2 mutation status (p = 0.8180) or the platinum sensitivity/resistance status of the tumors (p = 0.2899).

Conclusion. High MUC16 gene expression levels are associated with reduced progression-free survival and paclitaxel resistance, suggesting its potential as an unfavorable prognostic and predictive marker. Thus, determining MUC16 gene expression levels prior to therapy may have clinical potential for disease prognosis and for identifying patients for whom taxane-based treatment will likely be ineffective.

Introduction. Malignant neoplasms of the transverse colon, stomach and rectum are some of the most common oncological diseases. In Russia, their incidence is about 60,000 cases a year. Therefore, prediction of tumor recurrence or progression after treatment using biological markers is very important.

Aim. To study percentage of lymphocytes with asynchronous DNA replication (LAR) of the AURKA and TP53 genes in the peripheral blood of patients with malignant neoplasms of the gastrointestinal tract after treatment.

Materials and methods. Asynchronicity of the AURKA and TP53 genes in peripheral lymphocytes was measured using fluorescent in situ hybridization (FISH). In patients with malignant neoplasms of the gastrointestinal tract, interphase FISH analysis was performed prior to treatment and during the 5-year period after treatment.

Results. One year after treatment, percentage of LAR of both AURKA (34.4 % versus 28.8 %) and TP53 (26.1 % versus 21.0 %) genes significantly decreased compared to the values prior to treatment (p < 0.05). In patients without disease progression, mean group amount of LAR of both genes did not change in the 1–5-year period. In patients with disease progression, mean group values of LAR percentage of both genes were significantly higher than in the group without progression post-treatment (р < 0.01). In some patients, disease progression was diagnosed 1–13 months after LAR study. In the group before progression, LAR of AURKA and TP53 genes were also higher and differed from the value in the progression-free group (33.8 % versus 30.4 % and 25.3 % versus 21.7 %, respectively) (р < 0.05).

Conclusion. Analysis of LAR dynamics of the AURKA and TP53 genes in the long-term period after treatment showed that persistent high LAR levels of both genes can serve as a potential individual markers of disease progression.

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.