Features of gene copy number variation regulating mitochondrial function in endometrial cancer patients with type 2 diabetes mellitus.

Abstract

e17630 Background: Endometrial cancer (EC) holds a leading position among oncogynecological diseases. Type 2 diabetes mellitus (T2DM) is detected in a significant proportion of patients with EC and is associated with an unfavorable prognosis. Mitochondrial dysfunction plays a key role in the pathogenesis of both conditions. An important mechanism influencing mitochondrial function through altered gene expression and protein dysfunction is copy number variation (CNV). The aim of this study was to conduct a comparative analysis of the relative gene copy number of genes regulating mitochondrial function in EC patients with and without T2DM. Methods: The study included 71 patients with morphologically verified adenocarcinoma of the endometrium, stage 1a-1b, stratified into groups by tumor grade: G1 (n=20), G2 (n=35), and G3 (n=16). The mean age of the patients was 58.3 ± 8.7 years. Within each grade group, subgroups with and without T2DM were identified. The relative copy number of 13 genes (MT-CO1, mtTFB, mtSSB, ATAD3, TFAM, POLG, POLRMT, TOP1MT, MGME1, TEFM, MT-RNR2, GCAT, NRF1) was determined in DNA samples from tumor tissue using real-time quantitative PCR. Control samples consisted of histologically normal endometrial tissue obtained from patients undergoing surgical treatment for uterine fibroids. The Mann-Whitney U test with Bonferroni correction for multiple comparisons was used to compare quantitative measures between groups. Differences were considered statistically significant at p < 0.05. Results: A significant decrease in mitochondrial gene CNV was observed in tumor tissue compared to normal tissue in EC patients, which was more pronounced in the presence of T2DM. The most significant changes were noted for the genes MT-CO1 (decrease of 16.7-55.6%), TFAM (decrease of 60.0-68.8%), and NRF1 (decrease of 60.0-62.5%). In the G1 group with T2DM, copy numbers decreased relative to conditionally normal tissue to 0.5 for MT-CO1, 0.4 for mtSSB, and 0.3 for MT-RNR2. In the G2 group with T2DM, decreases to 0.4 for MT-CO1, 0.3 for mtTFB, and 0.2 for NRF1 were observed. The G3 group with T2DM showed the most pronounced reductions: MGME1 copy number decreased 5.0-fold, mtSSB 5.0-fold, and mtTFB 3.3-fold. Conclusions: The presence of T2DM in EC patients is associated with a significant reduction in CNV for genes regulating mitochondrial functions. These alterations vary depending on tumor grade and are most pronounced in poorly differentiated tumors (G2-G3). The obtained data elucidate molecular mechanisms underlying the more aggressive course of EC in comorbid T2DM and justify the need for developing personalized therapeutic approaches that account for the patients' metabolic status.