THE METHYLATION STATUS ROLE OF FIVE 3p21.31 REGION GENES IN THE MOLECULAR SUBTIPS OF BREAST CANCER PATHOGENESIS

In the last decade it was shown that in a multistage process of tumor formation, the alterations of cellular genes can occur not only as a result of genetic events (point mutations, deletions, amplifications), but also as a result of epigenetic changes, including local DNA hypermethylation. For last period, for the identification of hypermethylated regions of DNA have been used methods, based on the differential methylation status of CpG islands in normal and tumor cells. Aim. The aim of this study is to assess the methylation status of the tumor-associated genes group RASSF1A, RHOA, GPX1, DAG1 and USP4 in various biological subtypes of breast cancer, and also to assess their connection with the clinical course of the disease. Methods. Methylation status analysis was performed on 174 paired samples of the tumor and the adjacent histologically unchanged tissue from the patients with breast cancer and 20 breast tissue samples from healthy women. Two independent methods were used: methylation specific PCR (for RASSF1A) and methyl sensitive restriction analysis (for RHOA, GPX1, DAG1 and USP4).
Results. A statistically significant higher frequency of methylation of the RASSF1A, GPX1 and DAG1 genes in the tumor was shown compared to that in the histologically normal tissue (p<0,00001, p=0,0327 and p=0,0374, respectively). An interesting fact is that in the group of patients without methylation of the RASSF1A genes, 5- and 10-year survival was 93,5%
and 85,5%, respectively, and with methylation it decreased to 80,3% and 65,3% (p=0,007), respectively.
Conclusion. Methylation of the genes RASSF1A, GPX1, DAG1 plays an important role in the pathogenesis of luminal breast cancer, changing the functional activity of these genes. Methylation of RASSF1A genes is associated with an adverse clinical outcome of breast cancer. Epigenetic changes of these genes in combination or separately can be included in the biomarker system, which could help in the diagnosis, prognosis of the disease, and especially in the development of individual tactics for the treatment of breast cancer.