THE ROLE OF METHYLATION OF A GENE GROUP’S ОF THE SHORT ARM OF CHROMOSOME 3 IN DIAGNOSTICS AND PROGNOSIS OF BIOLOGICAL SUBTYPES OF BREAST CANCER

Abstract

Breast cancer (BC) is the multifactorial disease where different genes play the major pathogenic role with tumor-suppressor genes in particular. These genes methylation is supposed to be the common regulation mechanism. The aim of the present paper is to study methylation in group of tumor-suppressor genes: RASSF1A, SEMA3B, RARP2, RHOA, GPX1 and NKIRAS1 in luminal and mioepithelial breast cancer, and to evaluate their correlation with clinical subtype's course of this disease. Methods. Analysis of methylation was done in group of 174 malignant/normal breast tissue pairs and of 10 health breast tissue samples. Two independent methods a methyl-specific PCR (RASSF1A, RARP2, SEMA3B) and methylation-sensitive restriction analysis (RHOA, GPX1, NKIRAS were used. Results. A statistically significant high methylation frequency for genes RASSF1A, SEMA3B and RAR-p2 were shown (the positive ratio ranged from 13.2% to 37.9%) compared with normal breast tissue (the positive ratio ranged 0-6.9%, respectively), (p<0.00001). We revealed high frequent methylation level of RAR-P2 gene that was significantly higher in the luminal subtype B with the over expression of Her2 and Ki-67 compared with Her2-negative type and low level of Ki-67 (44% vs. 23.1%, p = 0.0458 and 38.5% vs. 16.2%, p = 0.0059, respectively). Interestingly we report that 5 and 10 years survivability without methylation was 93.5%, 85.5%, and 91.3%, 83.7%, respectively, compared ones with methylation where was lower 80.3 %, 65.3% (p = 0.007) and 84.3%, 67.2% (р=0,038) respectively. Conclusion. Methylation of RASSF1A, SEMA3B, RAR-P2, GPX1, RHOA и NKIRAS1 genes plays important role in tumorigenesis of luminal breast cancer by modulating their functions. Methylation of the RASSF1A and RAR-P2 genes is associated with an unfavorable the disease outcome. Identified epigenetic alterations in luminal subtypes BC could be included in the biomarker system to improve in evaluating diagnosis, prognosis of disease, especially for choosing the individual tactics of treatment.