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. Author manuscript; available in PMC: 2014 Dec 1.
Published in final edited form as: Clin Cancer Res. 2014 Apr 8;20(11):2898–2909. doi: 10.1158/1078-0432.CCR-13-3052

Figure 4. Molecular taxonomy of IDH-mutant glioma progression.

Figure 4

We propose that IDH-mutant gliomas develop and progress through an ordered sequence of oncogenic alterations. IDH-mutant gliomas are initiated by the occurrence of IDH1 or IDH2 mutation and widespread hypermethylation of CpG islands (CpG island methylator phenotype, CIMP) in a glial progenitor cell population. The subsequent acquisition of TP53 and ATRX mutations results in development along an astrocytoma pathway whereas the codeletion of 1p and 19q (t1;19) along with CIC, FUBP1 and TERT mutations result in the formation of oligodendrogliomas. After acquisition of these “lineage-defining” mutations, IDH-mutant astrocytomas and oligodendrogliomas may follow several “tertiary” genetic pathways during the transformation to malignant or high-grade tumors. Astrocytomas tend to amplify growth receptor genes such as PDGFRA and MET, whereas oligodendrogliomas tend to develop activating mutations in intracellular signaling genes such as PIK3CA and KRAS. Alternative tertiary pathways include Myc activation and other undescribed mutations. Acquisition of tertiary genetic alterations may result in more malignant behavior. RTK, receptor tyrosine kinase; PI3K, Phosphoinositide 3-kinase; MAPK, mitogen-activated protein kinase.