Promoter methylation of glutathione S-transferase π1 and multidrug resistance gene 1 in bronchioloalveolar carcinoma and its correlation with DNA methyltransferase 1 expression

Abstract

BACKGROUND: The presence of glutathione S-transferase (GST) π1 (GSTP1) or multidrug resistance gene 1 (MDR1) promoter methylation in lung cancer was studied for the first time to the authors' knowledge; and, to date, the clinical significance of methylation is not clear. The objective of the current study was to determine the promoter methylation status of GSTP1 and MDR1, which encode GST-π and P-glycoprotein (Pgp), respectively, in patients with bronchioloalveolar carcinoma (BAC) and to investigate whether methyltransferase 1 (DNMT1)-mediated GSTP1 or MDR1 methylation are responsible for disease progression and prognosis in patients with BAC. METHODS: Protein expression levels of DNTM1, GST-π, and Pgp were determined by immunohistochemistry in samples from 36 patients with BAC. Promoter methylation status of the GSTP1 and MDR1 genes was determined by using methylation-specific polymerase chain reaction analysis. RESULTS: The results demonstrated a significant correlation between the methylation of the GSTP1 or MDR1 promoters and negative expression of their respective proteins in BAC (P < .05). A significant correlation also was demonstrated between GSTP1 methylation and recurrence-free and overall survival of patients with BAC. DNMT1 protein expression levels were correlated with GSTP1 promoter methylation and patient prognosis (P < .05). However, no correlation was observed between DNMT1 expression and MDR1 methylation. CONCLUSIONS: GSTP1 promoter methylation mediated by DNMT1 may promote BAC progression and could serve as a poor prognostic indicator for patients with this disease. DNMT1 protein expression also may be considered as a prognostic indicator. Methylation of the MDR1 promoter may be mediated through pathways other than DNMT1 in BAC and does not appear to be associated with disease progression or patient prognosis. © 2009 American Cancer Society.