The MGMT gene encodes the O-6-methylguanine-DNA methyltransferase, an enzyme involved in DNA repair. This protein functions as a transferase and as a acceptor of an alkyl-group; it removes promutagenic alkyl groups from the O6 position of guanine in DNA. It repairs O-6-alkylguanine lesions stoichiometrically without a multi-enzymatic pathway and self-inactivates. The expression of MGMT can be induced by glucocorticoids, cyclic AMP, protein kinase C, DNA damage, and through interaction of several transcriptional factors, including SP1, activator proteins 1 and 2 (AP-1, and AP-2), with its promoter region. MGMT activity varies significantly in normal and tumor tissue; it is epigenetically silenced in various human tumors.
Epigenetic silencing of the MGMT gene by promoter methylation has been shown to be a poor prognostic factor, but a good predictive marker for chemotherapy when alkylating agents are used. It has also been associated with longer overall survival in patients with glioblastoma who received alkylating chemotherapy with carmustine or temozolomide.
The MGMT gene is located on chromosome 10q26. It consists of five coding exons and four introns and spans a region greater than 300 kb; the promoter region spans 1.2 kb and includes the first exon and part of the first intron. The encoded protein, MGMT, is 207 amino acids in length and weights about 21.65 kDa. The MGMT protein has been conserved through evolution.
To date, 438 polymorphisms have been found in this gene. Some of these polymorphisms alter the protein and may be useful as diagnostic tools, pre-treatment factors and indicators of risk of having a tumor. The most common variants of MGMT are p.Ile143Val and p.Lys178Arg, accounting for 20% of the variations.
Mokhtar et al. (2014) undertook a study to profile the methylation status of DNA repair gene O6-methylguanine DNA methyltransferase (MGMT) and its protein expression in thymic epithelial tumors in 66 samples. They found that MGMT methylation was significantly more frequent in thymic carcinoma than in thymoma (17/23, 74% versus 13/44, 29%; P<0.001). Loss of expression of MGMT protein was significantly more frequent in thymic carcinoma than in thymoma (20/23, 87% versus 10/44, 23%; P<0.0001). Mokhtar et al. (2014) also found a significant correlation between of MGMT methylation and loss of its protein expression (P<0.0003). They also noticed that MGMT methylation and loss of expression were significantly more frequent in advanced thymic epithelial tumors (III/IV) than in early tumors (I/II).
Al-Kuraya et al. (2005) conducted a retrospective cohort study based on 100 Diffuse Large B Lymphoma (DLBCL) tumor samples collected between 1990 and 2000 in Saudi Arabia. Methylation specific PCR was used to analyze the MGMT promoter methylation status. In addition, a tissue microarray of these samples was also constructed. MGMT hypermethylation was found in 71% of the samples, and was found to be associated with absent MGMT protein expression. MGMT methylation status was also found to be strongly associated with overall survival, with increasing survival among patients with samples with increased methylation. Similar results were found by the study of Al-Kuraya et al. (2006), which included samples from 190 Arabian patients with DLBCL. MGMT hypermethylation was found to be strongly associated with prolonged survival. In addition, multivariate analysis, including immunophenotype and MGMT methylation revealed an independent prognostic significance for MGMT methylation.
Siraj et al. (2007) conducted a study among Saudi patients with DLBCL. A total of 160 DLBCL patients (107 men, 43 women) and 511 Saudi control subjects were included in the study. All samples were analyzed for MTHFR C677T and A1298C functional polymorphisms using restriction fragment length polymorphism in association with MGMT and FHIT genes promoter hypermethylation. No association was found between the MTHFR variants and MGMT or FHIT hypermethylation in DLBCL.