Advances in Molecular Oncology

Introduction. Uterine cancer is a leading gynecologic oncology morbidity. Early prediction of metastatic disease is critical for treatment decisions. Therefore, the search for minimally invasive molecular markers for predicting metastasis is a pressing issue. Promising biomarkers in this regard include gene copy number values in circulating cell-free DNA (cfDNA) in plasma.

Aim. To analyze the relative copy number of genes regulating mitochondrial function in plasma of uterine cancer patients to develop a minimally invasive method for predicting metastasis.

Materials and methods. The bioinformatics phase of the study identified a list of genes associated with mitochondrial dysfunction and abnormal copy number in uterine cancer. The study included 98 patients diagnosed with adenocarcinoma of the corpus uteri (G₁ (n = 43), G₂ (n = 35) and G₃ (n = 20)), 15 patients with uterine myoma and 20 conditionally healthy donors. The relative copy number of 13 genes was determined by quantitative real-time polymerase chain reaction on cfDNA samples from blood plasma. ROC analysis and LASSO-penalized (LASSO – Least Absolute Shrinkage and Selection Operator) logistic regression were used to select markers.

Results. A significant decrease in relative copy number of mtSSB, MT-RNR2, NRF1, MGME1, and MT-CO1 in plasma was revealed in uterine cancer patients (p <0.005) with a metastatic course of the disease, moreover, the degree of change in copy number increased from G₁ to G₃. LASSO regression analysis enabled the selection of three genes: mtSSB, MT-RNR2, and MGME1. The combined panel achieved an area under the curve (AUC) of 0.98 (95 % confidence interval 0.96–1.00), a sensitivity of 95 %, and a specificity of 92 % for predicting metastases.

Conclusion. Thus, determination of the copy number of the mtSSB, MT-RNR2 and MGME1 genes in blood plasma has potential for use in minimally invasive prediction of metastatic lesions in uterine cancer.

Introduction. In recent years, a rising incidence of oral cancer (OC) has been observed among young adults without traditional risk factors (smoking, alcohol consumption, and human papillomavirus infection). An aggressive clinical course and a high recurrence rate are observed in patients of this age group. Therefore, there is a growing need to identify novel molecular alterations that could elucidate the mechanisms driving the disease progression. Previously, we identified mutations in the EPHB6 gene associated with early-onset OC recurrence.

Aim. To evaluate the effect of EPHB6 knockdown on the functional characteristics of OC cells in vitro.

Materials and methods. The OC cell line Cal-27 was used in this study. Gene knockdown was induced using small interfering RNAs.

Results. EPHB6 knockdown resulted in a 90 % reduction in gene expression relative to the control, which was accompanied by alterations in cellular functional properties, including inhibition of migration and invasion, as well as reduced tumorigenic capacity in three-dimensional cultures.

Conclusion. These findings shed light on the potential mechanisms by which EPHB6 contributes to early-onset OC progression.

Epigenetic mechanisms play a significant role in breast cancer (BC) pathogenesis and contribute to the tumor’s progression, metastasis and resistance to therapy. BC heterogeneity in large part is determined by unique epigenetic landscape created by various factors. However, despite obvious heterogeneity, modern therapeutic approaches in this disease are limited to evaluation of histological subtype, receptor status (estrogen, progesterone, human epidermal growth factor 2 receptors), and proliferative activity (Ki-67). All important oncogenes and tumor suppressor genes, as well as tumor microenvironment, are controlled by epigenetic factors, and study of these control mechanisms and identification of clinically significant epigenetic biomarkers is an important problem. Currently, there are thousands of studies on epigenetic regulation in BC, systematization of which will help to better understand complex mechanisms of carcinogenesis.

This review describes the main epigenetic mechanisms including DNA and RNA methylation, histone post-translational modification, and regulatory activity of non-coding RNAs. Characteristics of epigenetic regulation of various molecular and biological BC subtypes taking into account diagnostic and prognostic markers are analyzed, potential therapeutic targets are evaluated. The article also considers signaling pathways regulated by epigenetic modulators.

Plasminogen activator inhibitor type 1 (PAI-1) (serine protease inhibitor SERPINE1) belongs to the serine protease inhibitor superfamily and is found in many cell types, including megakaryocytes, platelets, adipocytes, endothelial cells, hepatocytes and smooth muscle cells. It is primarily studied as a regulator of the fibrinolytic system. In recent years, various functions of this protein have been discovered, and it is now considered an important component of many pathological processes and diseases, such as metabolic syndrome, chronic kidney disease, neuropsychiatric disorders and others. This serpin is one of the factors that determine the clinical course of infectious diseases. In the literature there is a justified statement about this protein: “serpin with a finger in many PAIs”. These findings suggest that PAI-1 may be a promising target for the treatment of various diseases. In addition, the role of this protein in oncogenesis has been studied for 40 years. The article provides an overview of current data on the role of PAI-1 in oncogenesis, the potentiation of chemotherapy and radiotherapy resistance of tumor cells, and the first experience in creating PAI-1 inhibitors in clinical oncology.

Epithelial ovarian cancer, primarily high-grade serous ovarian cancer, is a tumor characterized by a high probability of recurrence following primary treatment, which consists of cytoreductive surgery combined with platinum-based chemotherapy. Despite standardized therapeutic approaches, the platinum-free interval, progression-free survival, and overall survival vary substantially. Beyond somatic tumor characteristics and the completeness of cytoreduction, a significant portion of this variability may be driven by germline single-nucleotide polymorphisms (SNPs) in genes encoding proteins responsible for drug transport, detoxification, and DNA repair. The objective of this review is to systematize data on the molecular mechanisms of platinum sensitivity and resistance in serous ovarian cancer, with an emphasis on the role of germline structural DNA variants (SNPs), discuss the limitations of existing data, and outline directions for future research.

A literature search was performed in PubMed, Scopus and Google Scholar using the following keywords: “high-grade serous ovarian cancer”, “platinum”, “carboplatin”, “cisplatin”, “polymorphism”, “SNP”, “pharmacogenetics”, “progression-free survival”, and “platinum resistance”. Priority was given to studies with a sample size of ≥100 ovarian cancer patients and those with independent validation or a meta-analysis. A number of studies with smaller sample sizes were included due to the particular significance of their results and are specified in the text. The most reproducible associations with platinum resistance are demonstrated by SNPs in genes involved in nucleotide excision repair pathways (ERCC1, ERCC5), platinum transport and excretion (ABCB1), and specific signaling pathways (STAT3, FGFR4). Many candidate associations remain controversial owing to variations in the definition of platinum resistance, small sample sizes, heterogeneity in treatment regimens, and interethnic differences in allele frequencies and effects.