Genetics of Glioblastoma: Insights into Biology and Therapy Resistance

Abstract

The central nervous system contains the neural stem cells which differentiate and give rise to the neurons as well as the glial cells which are non-neuronal in nature and provide support and protection to neurons. Unlike neurons, glial cells do not lose the capacity to divide and are more abundant. The classification of neurological tumors is based on the predominant cell types. For example, astrocytoma is derived from astrocytes, oligodendroglioma is derived from oligodendrocytes, and oligoastrocytoma contains both astrocytic and oligodendroglial components. Glioblastoma (GBM) is the most aggressive and lethal form of astrocytoma. The treatment strategies include the maximal safe surgical resection of the tumor, followed by radiotherapy and chemotherapy using Temozolomide (TMZ). In spite, the median survival for the GBM patients still remains less than 15 months and recurrence occur in almost all the GBM cases. However, research from worldwide laboratories has led to identification of genetic determinants like MGMT (O6-methylguanine-DNA methyl transferase) and APNG (Alkylpurine–DNA–N-glycosylase) which govern the response of GBM patients to TMZ. Promoter methylation of MGMT has been associated with longer survival in GBM patients receiving TMZ. It is believed that the reason behind is the ability of MGMT to remove the TMZ induced methyl group from guanine. Similarly, base excision repair enzyme APNG, which repairs TMZ induced lesions N3-methyladenine and N7-methylguanine has also been reported to contribute to TMZ resistance. Hence, the objective of this study was to elucidate the factors which might modulate the response of GBM patients to TMZ