Hypermethylation of Long Noncoding RNA Genes GAS5, HOTAIR, HOTAIRM1, and SSTR5-AS1 as Factors in the Development and Progression of Metastatic Breast Cancer

Metastasis to the lymph nodes is one of the most important factors in the poor prognosis of patients with breast cancer; the five-year survival rate for metastatic breast cancer is less than 30%. DNA methylation occurs in the early stages of the development of cancer and also plays an important role in the development of lymphogenous metastases and can serve as a diagnostic and prognostic marker of breast cancer. The lncRNA genes GAS5, HOTAIR, HOTAIRM1, and SSTR5-AS1, presumably hypermethylated in breast cancer and associated with epithelial-mesenchymal transition and metastasis, were bioinformatically selected. Quantitative methyl-specific PCR showed a statistically significant increase in the methylation level of these lncRNA genes in breast tumors compared to the paired norm. Hypermethylation of the HOTAIRM1 and SSTR5-AS1 genes in breast cancer was identified for the first time. Using statistical analysis, positive correlations were established between methylation levels for the GAS5-HOTAIR and SSTR5-AS1-HOTAIRM1 pairs. The result of co-methylation of GAS5 and HOTAIR in breast cancer is consistent with the bioinformatically predicted (using enrichment analysis and the ncPath database) participation of these lncRNAs in the regulation of common signaling pathways and biological processes. The level of methylation of the lncRNA genes HOTAIRM1 and SSTR5-AS1 is associated with indicators of breast cancer progression (stage of the tumor process, tumor size, presence of metastases in the lymph nodes). A model has been proposed for assessing the risk of developing lymphogenous metastases depending on the level of methylation of the HOTAIRM1 gene. Thus, data were obtained on lncRNAs GAS5, HOTAIR, HOTAIRM1, and SSTR5-AS1 and hypermethylation of their genes as factors in the development and progression of metastatic breast cancer.