Prognostic Relevance of Promoter Hypermethylation of Multiple Genes in Breast Cancer Patients

Abstract

Background: Methylation-mediated suppression of detoxification, DNA repair and tumor suppressor genes has been implicated in cancer development. This study was designed to investigate the impact of concurrent methylation of multiple genes in breast tumors on disease prognosis.Methods: Methylation specific PCR was carried out to analyze the methylation status of seven genes in archived breast tissues and determine the effect of aberrant methylation of multiple genes on disease prognosis and patients’ survival.Results: Promoter hypermethylation was observed in PRB 67%, ERα 64%, RASSF1A 63%, p16INK4A 51%, PRBβ2 22%, GSTP1 25% and BRCA1 27% of the breast cancers, respectively. Concurrent methylation of BRCA1, ERα, GSTP1 and RARβ2, was observed in a large proportion of breast cancers analyzed, suggesting that these genes do not appear to be methylated alone. Patients with high methylation indices had poor prognosis (p < 0.001, Hazards ratio = 14.58). Cox regression analysis showed RARβ2 promoter methylation to be an independent important determinant of breast cancer prognosis.Conclusions: Our results suggest that methylation of multiple genes plays an important role in prognosis of breast cancer. Our study not only describes the association of methylation mediated silencing of multiple genes with the severity of disease, but also drives to speculate the molecular crosstalk between genes or genetic pathways regulated by them individually.

The high methylation level of a novel 151-bp CpG island in the ESR1 gene promoter is associated with a poor breast cancer prognosis

“…Until now, 87 distinct DNA methylation biomarkers had been reported; among them, 68 markers were analyzed once in a single population [ 48 ], exposing the need for biomarkers for a specific community as Mexican women. Some reports indicate that methylation at ESR 1 has no statistically significant correlation with BC outcome [ 15 , 41 , 49 – 52 ]. However, our findings suggested that methylation levels in the 151-bp island from that gene might be implemented to assist BC stratification.…”

Surface ligation-based resonance light scattering analysis of methylated genomic DNA on a microarray platform

“…P16 (INK4A) is one of the cyclin-dependent kinase inhibitors (CKIs) which play important roles in regulating cell cycles. 47 Abnormal methylation of the p16 gene, especially the promoter and exon regions of the gene, is closely related to the generation of cancers, such as colorectal cancer, 48 breast cancer 49 and lung cancer. 50 To assess the ability of the proposed surface ligation-based RLS method to quantitatively assay mimic samples, mimic oligonucleotides including six CpG sites (marked as #14, #26, #44, #48, #53 and #54, shown in Fig.…”