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

Abstract

BackgroundLow-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.MethodsWe 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.ResultsMGMT 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.ConclusionsThe 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.

Clinical Efficacy of Temozolomide and Its Predictors in Aggressive Pituitary Tumors and Pituitary Carcinomas: A Systematic Review and Meta-Analysis

“…Preliminary data proposed that DNA repair enzyme O6methylguanine DNA methyltransferase (MGMT) expression was correlated with the clinical benefit of TMZ in APT and PC patients (35). According to our previous research, the majority of prolactinomas showed minimal MGMT expression, which provide a rational for the utility of TMZ to manage the aggressive prolactinomas (36). MGMT may attenuate the effect of TMZ by removing additional alkyl groups.…”

“…In our study, patients with methylated MGMT promoter generate a higher radiological response, but the difference is not as significant as the effect of MGMT expression. It implies that MGMT expression level is not only affiliated with the promoter methylation status but also regulated by other unique epigenetic and transcriptional microenvironment factors (28,29,36). Moreover, the MGMT promoter methylation is simply classified as the positive group and the negative group without a cutoff of grading as definite as the gene expression, which might be the principal event for the reduction of correlation between MGMT promoter methylation and TMZ response (20).…”

Evaluation of 06-methylguanine-DNA methyltransferase expression in children and adolescent pituitary adenoma

“…A previous study reported low MGMT expression in 26% of functional PA in a cohort of adult-dominated patients [24]. Low MGMT expression was also reported in prolactinoma (78-85.71%) [36,37], corticotroph adenomas (62.5-81.48%) [37,38], and somatotroph adenomas (90.0-91.7%) [37,39]. In the current study, the functional PAs were 32/38 (84.21%), of which 13/32 (34.21%) showed low MGMT expression.…”

Is there a role for early chemotherapy in the management of pituitary adenomas?

“…In glioblastoma (GBM), low expression of MGMT as determined by immunohistochemistry has been associated with responsiveness to temozolomide; 16 however, only MGMT promoter methylation, which results in silencing of the MGMT gene, has been validated as a predictive and prognostic marker. 17 In pituitary adenomas, an inverse relationship between MGMT promoter methylation and MGMT expression has been reported by some, 18,19 but not all, investigators. 20,21 At this time, the evidence primarily supports a relationship between treatment response and low MGMT expression by immunohistochemistry as opposed to MGMT promoter methylation, which is technically more reliable.…”