Abstract
O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and its subsequent loss of protein expression has been identified to have a variable impact on clinical outcome of glioma patients indicated for chemotherapy with alkylating agents (Temozolomide). This study investigated methylation status of MGMT gene along with in situ protein expression in malignant glioma patients of different histological types to evaluate the associated clinical outcome vis-a-vis use of alkylating drugs and radiotherapy. Sixty three cases of glioma were evaluated for MGMT promoter methylation by methylation-specific PCR (MS-PCR) and protein expression by immunostaining (IHC). Methylation status of MGMT and loss of protein expression showed a very high concordant association with better survival and progression free survival (PFS) (p < 0.0001). Multivariate Cox regression analysis showed both MGMT methylation and loss of protein as significant independent prognostic factors in glioma patients with respect to lower Hazard Ratio (HR) for better OS and PFS) [p < 0.05]. Interestingly concordant MGMT methylation and lack of protein showed better response in TMZ therapy treated patient subgroups with HR of 2.02 and 0.76 (p < 0.05). We found the merits of prognostication of MGMT parameters, methylation as well as loss of its protein as predictive factors for favorable outcome in terms of better survival for TMZ therapy.
Highlights
Cluster University, Srinagar, J & K, India
methylguanine-DNA methyltransferase (MGMT) promoter gene methylation followed by its subsequent protein inactivation has been substantiated to modulate response of chemotherapeutic drugs like alkylating agents (Temozolomide) commonly used in malignant gliomas
A number of clinical trials authenticated that MGMT methylated sequence serves as a strong prognostic factor for longer survival and progression free disease[25,26,27,28,29]
Summary
The MGMT, a potent DNA repair enzyme repairs alkylating lesions of the DNA by knocking out mutagenic adducts from the O6 position of guanine as usually caused by the Temozolomide, a chemotherapeutic agent used to treat Glioma[13] This influences the treatment in cells with intact MGMT gene and confers drug resistance. On the other hand the therapeutic response to alkylating agents is improved in tumor cells with hypermethylation in MGMT causing its silence resulting either in low levels or complete loss of MGMT expression[16] This phenomena causes MGMT promoter methylation to correlate with a survival benefit in glioma patients treated with alkylating chemotherapeutics[17]. MGMT promoter methylation represents part of a genetic signature of chemotherapeutically sensitive gliomas[18,19,20]
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