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World J Clin Cases. Dec 16, 2014; 2(12): 835-839
Published online Dec 16, 2014. doi: 10.12998/wjcc.v2.i12.835
Role of MGMT as biomarker in colorectal cancer
Alessandro Inno, Giuseppe Fanetti, Maria Di Bartolomeo, Stefania Gori, Claudia Maggi, Massimo Cirillo, Roberto Iacovelli, Federico Nichetti, Antonia Martinetti, Filippo de Braud, Ilaria Bossi, Filippo Pietrantonio
Alessandro Inno, Stefania Gori, Massimo Cirillo, Medical Oncology Department, Ospedale Sacro Cuore Don Calabria, Negrar, 37100 Verona, Italy
Giuseppe Fanetti, Radiotherapy Unit, European Institute of Oncology, 20100 Milan, Italy
Maria Di Bartolomeo, Claudia Maggi, Roberto Iacovelli, Federico Nichetti, Antonia Martinetti, Filippo de Braud, Ilaria Bossi, Filippo Pietrantonio, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20100 Milan, Italy
Author contributions: All authors gave substantial contributions to conception and design, acquisition of data, analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; final approval of the version to be published.
Correspondence to: Filippo Pietrantonio, MD, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 20100 Milan, Italy. filippo.pietrantonio@istitutotumori.mi.it
Telephone: +39-2-23903807 Fax: +39-2-23902149
Received: July 23, 2014
Revised: September 1, 2014
Accepted: October 14, 2014
Published online: December 16, 2014
Processing time: 147 Days and 16.6 Hours
Abstract

O6-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 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.

Keywords: Colorectal cancer; O6-methylguanine DNA methyltransferase; Temozolomide; Dacarbazine; Biomarker

Core tip: O6-methylguanine DNA methyltransferase (MGMT) methylation is involved in colorectal carcinogenesis and represents a predictive biomarker for alkylating agents in metastatic colorectal cancer. In fact, patients with chemorefractory metastatic colorectal cancer with MGMT methylation derived promising response from treatment with dacarbazine or temozolomide, and ongoing research is investigating the efficacy of temozolomide in combination with other chemotherapy drugs for MGMT-methylated colorectal cancer. Future challenges include the combination with biologic drugs and the research for additional biomarkers.