Each genetic subtype may demonstrate significant inter-tumor heterogeneity in terms of genetic lesions other than canonical IDH1/2, TP53, and TERT promoter mutations, and 1p/19q co-deletion [2]. Regional heterogeneity may be closely correlated with the history of clonal evolution, illustrating how a tumor expands outward from its origin, intermingling cells with different genetic mutations in the periphery, to increase overall heterogeneity. Despite the presence of parallel mutations involving common targets, prominent regional heterogeneity raises concern that sequencing of bulk tumor may not detect rare but important mutations or tumor cell subpopulations that exist at low levels.

For instance, an oligodendroglioma, IDH1 mut, 1p/19q co-del seems to arise from somewhere with IDH1, TERT promoter, and TCF12 mutations and 1p19q LOH and propagated to a common branch-point by acquiring mutations in CIC (p.R202W), FUBP1 (c.1041+1G>-), and FUBP1 (c.1706-1G>A). The tumor then further extends to a location with mutations in MLL3, ARID2, and ARID1B, another location with CIC (p.A235T) and SMARCC2 mutations, and the common branch with CIC p.Q172X, CIC p.T767fs, or to different directions with CIC p.R1515C and MLL2, frequently showing confluence in periphery between multiple components from surrounding branches.

This is also true in IDH-wild type gliomas; with the lack of common, canonical mutations, IDH-wild type gliomas are more heterogeneous than IDH-mutated gliomas [2, 3]. TERT promoter mutations have been demonstrated in Type-1 and Type-2 lower grade gliomas [8], and have a differential effect on progression free survival dependent on the 1p/19q codeletion status. Specifically, in IDH-wild type tumors the presence of a TERT promoter mutation correlated with a shorter progression free survival interval, while in IDH-mutated tumors, a TERT promoter mutation demonstrated an increased progression free survival. The interactions between 1p/19q codeletion, TERT promoter mutation, and other concurrent mutations are not yet completely understood, and a better delineation of the interactions of these mutations may help to further classify lower grade gliomas.