BlueCross BlueShield of Tennessee Medical Policy Manual

Analysis of MGMT (O6-methylguanine-DNA methyltransferase) Promoter Methylation


Malignant gliomas are the most common primary brain cancer in adults, with approximately 17,000 new cases diagnosed annually in the United States. Glioblastoma multiforme (GBM) is the most common type and despite treatment advances, prognosis for GBM remains poor, with less than 5% surviving beyond five years. For high-grade malignant gliomas, standard treatment combines surgical resection, postoperative radiation and chemotherapy using alkylating agents such as temozolomide (TMZ). Adjuvant options mainly depend on the performance status of the individual.

Testing for MGMT (O6-methylguanine-DNA methyltransferase) gene promoter methylation has been proposed as a method to predict which individuals with malignant gliomas may benefit from the use of TMZ. Gene methylation is a control mechanism that regulates gene expression.  In malignancies, gene promoter regions can have abnormal or increased levels of methylation, which can block gene function, leading to decreased or absent levels of the protein encoded by the gene. MGMT is a DNA repair protein that causes resistance to the effect of alkylating chemotherapy by removing alkylation of the O6 position of guanine, the most cytoxic lesion induced by alkylating chemotherapy agents. Aberrant methylation of the MGMT gene promoter region leads to loss of MGMT protein expression and reduced proficiency to repair DNA damage induced by alkylating chemotherapeutic agents, potentially increasing tumor susceptibility to alkylating agent-based chemotherapy.





A high frequency of MGMT promoter methylation was noted in long-term survivors of glioblas­toma who received repetitive alkylating chemotherapy during the course of the disease. Generally, carriers of the methylated form of the MGMT promoter respond sub­stantially better to therapy with temozolomide.  Despite its well-established role in carcinogenesis, studies have not demonstrated MGMT promoter methylation status as an effective prognostic tool or biomarker in cancers other than high-grade gliomas.

SOURCES Centers for Medicare & Medicaid Services. Palmetto GBA. (2019, November). LCD: MolDX: MGMT promoter methylation analysis (L35974). Retrieved March 5, 2020 from

Dullea, A., & Marignol, L. (2016). MGMT testing allows for personalized therapy in the temozolomide era. Tumour Biology, 37 (1), 87-96. Abstract retrieved July 27, 2016 from PubMed database.

Nassiri, F., Taslimi, S., Wang, J.Z., Badhiwala, J.H., Dalcourt, T., Ijad, N., et al. (2020). Determining the optimal adjuvant therapy for improving survival in elderly patients with glioblastoma: a systematic review and meta-analysis. Clinical Cancer Research, doi: 10.1158/1078-0432.CCR-19-3359 [Epub ahead of print]

National Comprehensive Cancer Network. (2020, September). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Central nervous system cancers V 3.2020. Retrieved November 25, 2020 from the National Comprehensive Cancer Network.

National Institute for Health and Clinical Evidence (NICE). (2018, July). Brain tumours (primary) and brain metastases in adults. Retrieved November 25, 2020 from

Perry, J., Laperriere, N., O’Callaghan, C., Brandes, A., Menten, J., Phillips, C., et al. (2017). Short-course radiation plus temozolomide in elderly patients with glioblastoma. New England Journal of Medicine, 376, 1027-1037. (Level 2 evidence)

Zarnett, O.J., Sahgal, A., Gosio, J., Perry, J., Berger, M.S., Chang, S., & Das, S. (2015). Treatment of elderly patients with glioblastoma: a systematic evidence-based analysis. Journal of the American Medical Association - Neurology, 72 (5), 589-596. Abstract retrieved September 15, 2015 from PubMed database.  




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