The understanding of molecular subtypes of gliomas led to the World Health Organization Classification of Tumors of the Central Nervous System 2016 classification criteria for these tumors, introducing the concept of primary glioblastoma and secondary glioblastomas based on genetic alterations and gene or protein expression profiles. Some of these genetic alterations are currently believed to have clinical significance and are more related to secondary GBMs: TP53 mutations, detectable in the early stages of secondary GBM (found in 65%), isocitrate dehydrogenase 1/isocitrate dehydrogenase 2 mutations (50% of secondary GBMs), and also O6 methylguanine DNA methyltransferase (75% of secondary GBMs) 1).
Genetic mapping of the GBM genome has unveiled countless significantly mutated genes; although many of these mutations contribute to glioma progression, therapeutic-specific modalities require further investigation 5) 6) 7).
Several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer 8).
Genomewide mutational analysis of glioblastomas revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas).
Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas 9).