Anatomic Predilection of IDH-Mutant Gliomas: A Multi-Institutional Spatial Analysis

IntroductionInteractions between cancer cells and their microenvironment are central to tumor formation. Regional microenvironmental variability in the brain may offer insight into essential factors in tumorigenesis. Surprisingly, a granular assessment of regional patterns of gliomagenesis has not been undertaken in the molecular era. ObjectiveTo quantitatively establish the anatomical distribution of the major molecular subtypes of adult diffuse glioma. MethodsWe retrospectively analyzed a consecutive series of 204 IDH-mutant and 200 IDH- wildtype gliomas. Tumor volumes were segmented, normalized, and assigned to a brain location using a standardized neuroanatomic atlas. An independent and external validation cohort of 190 IDH-mutant and 227 IDH-wildtype gliomas was used to assess reproducibility. Microarray expressions from the Allen Human Brain Atlas were utilized to analyze transcriptomic differences between hotspots and coldspots of IDH-mutant gliomas. Results50.5% (103/204) of IDH-mutant tumors arose with the superior and middle frontal gyri indicating a 3.1-fold regional enrichment relative to the volume of these gyri (p<0.001). Only 0.5% (1/204) of IDH-mutant tumors arose with the occipital gyri indicating a 23.4-fold regional scarcity relative to volume (p<0.001). 9.5% (19/200) of IDH-wildtype tumors arose in the superior temporal gyrus with a 2.1-fold enrichment (p=0.01) and 6% (12/200) in the hippocampus with a 6-fold enrichment (p<0.001). IDH-mutant and wildtype tumors were enriched by 4 and 4.5-fold respectively in the insula (both p<0.001). Both IDH-mutant astrocytomas and oligodendrogliomas were significantly enriched in the SFG (39.2% and 40.2% respectively; both p<0.001), but 23.5% (24/102) of astrocytomas occurred disproportionately higher in the insula compared to oligodendrogliomas (p<0.001). These enrichment patterns were reproduced in an independent validation cohort of 417 glioma patients. Transcriptomic analysis comparing the lobar hotspot (frontal lobe) to the coldspot (occipital lobe) revealed frontal enrichment of cholesterol (NES=1.78) and fatty acid (NES=1.94) metabolism pathways, paralleling the observed regional enrichment of IDH-mutant gliomas. ConclusionsThis study reveals striking regional differences in glioma incidence, identifying key hotspots in the brain for gliomagenesis that vary based on tumor molecular subtype. Metabolic differences across cortical regions raise the possibility that regional metabolic differences may contribute to the observed vulnerability of specific regions to gliomagenesis. These findings provide a framework for investigating additional microenvironmental factors that drive human glioma formation.