Reduction of GSTP1 expression by DNA methylation correlates with clinicopathological features in pituitary adenomas.

Pi-class glutathione-S-transferase (GSTP1) located on chromosome 11q13 encodes a phase II metabolic enzyme that detoxifies reactive electrophilic intermediates. GSTP1 plays an important role in the protecting cells from cytotoxic and carcinogenic agents and is expressed in normal tissues at variable levels in different cell types. Altered GSTP1 activity and expression have been reported in many tumors and this is largely due to GSTP1 DNA hypermethylation. The role of GSTP1 in pituitary tumorigenesis has not been investigated. In this study, we evaluated the GSTP1 expression level and GSTP1 DNA methylation status in a series of pituitary adenomas. Using immunohistochemistry, we identified expression of GSTP1 in all of the various normal hormone-producing adenohypophysial cell types. In pituitary adenomas, loss or reduced expression of GSTP1 was detected in 27 of 53 tumors (50.9%). Expression of GSTP1 was significantly lower in invasive adenomas than in noninvasive adenomas (P<0.05). Using methylation-specific polymerase chain reaction (MS-PCR), GSTP1 DNA promoter hypermethylation was detected in adenomas (38 of 53, 71.7%) but not in normal tissues. GSTP1 methylation was more frequent in grade II, III, and IV tumors (66.7, 85, and 83%, respectively) than in grade I tumors (33%, P<0.05). In addition, the frequency of GSTP1 methylation was higher in invasive tumors (85%) than in noninvasive tumors (59%; P<0.05). Methylation status correlated with significant downregulation of GSTP1 expression; the frequency of GSTP1 methylation was higher in tumors with reduced-GSTP1 expression (85%) than in tumors with normal or high GSTP1 expression (54%; P<0.05). These data indicate that GSTP1 inactivation through CpG hypermethylation is common in pituitary adenomas and may contribute to aggressive pituitary tumor behavior.