Expression profiling of O6 methylguanine-DNA-methyl transferase in prolactinomas: A correlative study of promoter methylation and pathological features in 136 cases

Abstract

Background: Low-level expression of O6 methylguanine-DNA-methyl transferase (MGMT) prolactinomas has been noted previously in case reports, although what modulates MGMT expression remains unclear. This study therefore aimed to delineate the factors regulating MGMT expression in prolactinomas. Methods: We retrospectively reviewed 136 prolactinoma patients who were treated in our center between January 2000 and September 2013. Expression of MGMT, Ki-67, and p53 protein were examined by immunohistochemical staining, and MGMT promoter methylation evaluated with methylation-specific PCR. Results: MGMT immunopositivity was <25 % in 106/136 tumor specimens (77.94 %). MGMT immunoexpression was positively correlated with age (r = 0.251, p = 0.003), but inversely correlated with p53 staining (r = -0.153, p = 0.021). Moreover, reduced MGMT expression was more frequent in atypical prolactinomas (p = 0.044). Methylated MGMT promoter was confirmed in 10/46 specimens (21.7 %), all of which had low level or absent MGMT staining. Both p53 protein (r = -0.33, p = 0.025) and promoter methylation (r = -0.331, p = 0.025) were negatively associated with MGMT expression. Multivariate logistic analysis indicated that age (odds ratio [OR] = 1.127. 95 % confidence interval [CI] 1.027-1.236, p = 0.012) and p53 (OR = 0.116. 95 % CI 0.018-0.761, p = 0.025) staining were independent determents of MGMT expression. Conclusions: The majority of prolactinomas, especially atypical prolactinomas, showed low-level or no MGMT immunoexpression, providing a rationale for the utility of temozolomide as an alternative to managing prolactinomas. In summary, epigenetic and transcriptional regulation are involved in silencing MGMT expression.