Epigenetic tumor heterogeneity and prognostic outcome in glioblastoma
Glioblastoma (GBM), the most common malignant glioma, is marked by its extensive intratumoral heterogeneity contributing to its aggressive nature, resistance to therapy, and inevitable recurrence. Despite the clinical prevalence of GBM, prognosis remains poor and treatment options are limited. Following surgical resection of the tumor, the drug Temozolomide (TMZ) is typically used for first-line treatment of GBM in conjunction with radiotherapy. TMZ is an orally bioavailable and BBB-penetrating alkylating chemotherapy. Approximately 30% of GBM exhibit hypermethylation of the promoter for the O-6-mehylguanine-DNA methyltransferase (MGMT) gene, a DNA repair enzyme that remediates the damage from TMZ. Epigenetic silencing of MGMT has been well characterized as a prognostic marker correlating with greater tumor sensitivity to TMZ and better patient outcome. However, the heterogeneous nature of GBM makes MGMT expression variable throughout the tumor. To this end, we have performed DNA methylation assays on samples taken from patient tumors in order to characterize the intratumoral heterogeneity of the methylation status of the MGMT promoter. A PCR-based approach was undertaken to screen 339 patient samples for MGMT promoter methylation status. Thus far, significant heterogeneity has been observed throughout multiple tumors in our patient cohort, and furthermore, within distinct regions of individual tumors. While this genetic variability poses an issue for current treatment approaches, further investigation of tumor heterogeneity with regards to MGMT promoter methylation and other genetic and epigenetic features may be applied to the development of more effective, personalized GBM treatments.
