International Journal of Cancer and Oncology | 2015-05-13

Methylation in glioma

Moritz C. Oberstadt

Abstract

Glioblastoma multiforme (GBM) is still the most aggressive primary brain tumor in adults. Despite advances in therapy, glioblastoma remains associated with poor prognosis and an overall survival time of 15 months. The short survival time is probably caused by the resistance of the tumor to the administered chemotherapy. Epigenetic alterations may be one of several changes in the tumor, which influence the chemoresistance. The most prominent epigenetic alteration in glioma is the DNA methylation. The Glioma CpG island DNA methylator phenotype (G-CIMP) is characterized as a specific DNA methylation pattern in a subset of genes restricted to gliomas and involved in the classification system of glioblastomas as part of the proneural subtype. Further, a significant prognostic impact could be shown for the methylation of the O6-methylguanine-DNA-methyltransferase (MGMT). The MGMT functions as a DNA repair enzyme, which repairs alkylating lesions of the DNA by removing mutagenic adducts from the O6 position of guanine, e.g. caused by the chemotherapeutic agent temozolomide. Hence, it confers drug resistance and the therapeutic response to alkylating agents is improved in tumor cells expressing low levels of MGMT. Furthermore, MGMT promoter methylation was demonstrated to result in decreased MGMT expression and correlates with a survival benefit in glioblastoma patients treated with alkylating chemotherapeutics such as temozolomide.