Prognostic relevance of promoter hypermethylation of multiple genes in breast cancer patients.
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%, ERalpha 64%, RASSF1A 63%, p16INK4A 51%, RARbeta2 22%, GSTP1 25% and BRCA1 27% of the breast cancers, respectively. Concurrent methylation of BRCA1, ERalpha, GSTP1 and RARbeta2, 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 RARbeta2 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.
Sharma
Gayatri
G
Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
Mirza
Sameer
S
Yang
Yi-Hsin
YH
Parshad
Rajinder
R
Hazrah
Priya
P
Datta Gupta
Siddartha
S
Ralhan
Ranju
R
D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D018899:CpG Islands / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction / Q000706:statistics & numerical data; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016016:Proportional Hazards Models; D011980:Receptors, Progesterone / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047628:Estrogen Receptor alpha; C533416:RARB2 protein, human; C411762:RASSF1 protein, human; D011980:Receptors, Progesterone; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C097314:progesterone receptor B; D051549:Glutathione S-Transferase pi