prognostic relevance of promoter hypermethylation of multiple genes in breast cancer patients

• DOI: 10.3233/clo-2009-0507
• Publication Date: 2009-01-01
• Authors: Ranju Ralhan; Priya Hazrah; Gayatri Sharma; Rajinder Parshad; Yi-Hsin Yang; Siddartha Datta G...; Sameer Mirza
• Keywords: Adult; Receptors, Retinoic Acid; Breast Neoplasms; Kaplan-Meier Estimate; Polymerase Chain Reaction; 03 medical and health sciences; 0302 clinical medicine; Humans; Genetic Predisposition to Disease; Promoter Regions, Genetic; RC254-282; Cyclin-Dependent Kinase Inhibitor p16; Neoplasm Staging; Proportional Hazards Models; QH573-671; BRCA1 Protein; Estrogen Receptor alpha; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; DNA Methylation; Middle Aged; Prognosis; 3. Good health; Glutathione S-Transferase pi; CpG Islands; Female; Other; Cytology; Receptors, Progesterone

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.