MGMT promoter methylation and immunoexpression in aggressive pituitary adenomas and carcinomas

Abstract

MGMT promoter hypermethylation of aggressive pituitary adenomas and pituitary carcinomas and low protein expression are implicated in improved response to treatment with temozolomide (TMZ). The aim of the present study was to investigate MGMT promoter methylation and immunoexpression in an aggressive subset of pituitary adenomas and carcinomas. Our material consisted of 12 silent subtype 3 (SS3) adenomas, 10 primary carcinomas, and 4 disseminated metastases. Two different tissue samples of 7 of the 12 SS3 adenomas and all carcinomas were analyzed for MGMT promoter methylation and immunohistochemical expression of MGMT. Immunoexpression was assessed semi-quantitatively as a percentage of immunoreactive nuclei. Overall 33% of carcinomas exhibited homogenous MGMT methylation in tumor and metastatic specimens. Low immunohistochemical MGMT expression was noted in 50% of carcinomas. Overall, 42% of the SS3 adenomas exhibited MGMT promoter methylation. MGMT immunostaining was predominantly negative (92%), with homogenous immunostaining results across different samples. Whereas all the methylated SS3 adenomas had low MGMT immunoreactivity, five unmethylated adenomas exhibited absent/low MGMT expression. There was no relationship between methylation status and MGMT immunoexpression was not apparent. MGMT methylation and low immunohistochemical expression seen in a subset of carcinomas and SS3 adenomas, suggesting that a subset of tumors may respond to treatment with TMZ. Heterogeneous MGMT methylation status in SS3 adenomas and the lack of concordance between methylation and immunohistochemical expression of MGMT suggest complex regulatory mechanisms, highlighting the need for improved methods in the research on a correlation between MGMT changes and response to TMZ.

DNA Mismatch Repair Protein (MSH6) Correlated With the Responses of Atypical Pituitary Adenomas and Pituitary Carcinomas to Temozolomide: The National Cooperative Study by the Japan Society for Hypothalamic and Pituitary Tumors

“…TMZ has been suggested to be effective also in pituitary adenomas harboring a methylated MGMT gene promoter, as is the case in gliomas (20,21). Salehi et al (22) reported that there was no relationship between MGMT promoter methylation status and MGMT immunoexpression. Although the changes in MGMT expression in recurring pituitary tumors could affect adenoma progression and TMZ efficacy, MGMT is not the sole molecular factor determining sensitivity to TMZ.…”

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

“…The value of MGMT status as a predictor of TMZ response in aggressive pituitary tumours is less clear. Promotor methylation of the gene occurs less frequently in pituitary tumours, and MGMT measured by PCR-based methods has not been associated with response to TMZ (11,102,107,111,130). The reasons are not understood and may involve mechanisms regulating MGMT expression independent of promotor methylation.…”

Aggressive Pituitary Tumors

“…A significant inverse correlation was found between IHC MGMT expression and response to TMZ; however, the absence of MGMT expression was not always predictive of tumor response [113,115]. On the contrary, studies examining MGMT promoter methylation in pituitary tumors confirmed its poor prognostic value since methylated MGMT promoter was found only in 60% of TMZ-sensitive tumors and 50% of TMZ-resistant tumors [96,119]. It appears that MGMT IHC but not MGMT promoter methylation status can be used to predict response to treatment in pituitary tumors.…”