MGMT

The DNA-repair protein O6-alkylguanine-DNA-alkyltransferase (AGT) is encoded by the gene O6-methylguanine-DNA-methyltransferase (MGMT).

AGT removes alkylating lesions at position O6 of guanine and therefore has an important role in maintaining normal cell physiology and genomic stability.

A broad range of expression of AGT is noted across tumours and normal tissues. Its expression also helps to prevent carcinogenesis and is a target for chemotherapy.

Overexpression of MGMT reduces the risk of carcinogenesis and the risk of mutations after exposure to methylating agents.

Loss of MGMT is associated with increased carcinogenic risk and increased sensitivity to methylating agents.

MGMT-promoter methylation shuts off MGMT expression in tumours and increases responsiveness to chemotherapy.

O6-benzylguanine is a specific inhibitor of AGT, but mutations in the active-site pocket of the protein can cause resistance to the drug.

MGMT genes with such mutations are effective for use in gene therapy for transducing drug resistance into haematopoietic stem cells, to protect these cells from the toxic effects of chemotherapy.

The physiological role of MGMT remains an area of active investigation.

The DNA-repair protein O6-alkylguanine DNA alkyltransferase (AGT) has a wide range of activity in normal tissues and its evolutionary conservation indicates a fundamental role in cell physiology and maintenance of the genome.

Through removal of alkylating lesions at O6 of guanine, AGT protects against mutagenesis and malignant transformation.

Pathology

 In tumours, AGT provides resistance to treatment with alkylating agents, unless expression is lost by methylation of the promoter of the gene encoding AGT - O6-methylguanine-DNA-methyltransferase (MGMT) - or there is direct inhibition of AGT activity.

 colorectal cancer

• O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer.
• Its prognostic role has not been defined yet, but loss of expression of MGMT, which is secondary to gene promoter methylation, results in an interesting high response to alkylating agents, such as dacarbazine and temozolomide.
• In a phase 2 study on heavily pre-treated patients with MGMT methylated metastatic colorectal cancer, temozolomide achieved about 30% of disease control rate.
• Activating mutations of RAS or BRAF genes as well as mismatch repair deficiency (MMR deficiency) may represent mechanisms of resistance to alkylating agents, but a dose-dense schedule of temozolomide may potentially restore sensitivity in RAS-mutant patients.
• Further development of temozolomide in MGMT methylated colorectal cancer includes investigation of synergic combinations with other agents such as fluoropyrimidines and research for additional biomarkers, in order to better define the role of temozolomide in the treatment of individual patients.

 brain tumors

• The molecular profiling of brain tumors, including testing for MGMT promoter methylation and chromosome 1p/19q deletion, can provide both diagnostic and prognostic information that may guide treatment.

Open reviews

 Aberrant methylation patterns in cancer: a clinical view. Paska AV, Hudler P. Biochem Med (Zagreb). 2015 Jun 5;25(2):161-76. doi : 10.11613/BM.2015.017 eCollection 2015. Review. PMID: 26110029 (Free)

 Role of MGMT as biomarker in colorectal cancer. Inno A, Fanetti G, Di Bartolomeo M, Gori S, Maggi C, Cirillo M, Iacovelli R, Nichetti F, Martinetti A, de Braud F, Bossi I, Pietrantonio F. World J Clin Cases. 2014 Dec 16;2(12):835-9. doi : 10.12998/wjcc.v2.i12.835 Review. PMID: 25516857 (Free)