Multi-institutional analysis shows specific tumor distribution in regions like superior frontal gyrus, indicating implications for tumor–microenvironment interactions.
BACKGROUND The anatomical origins of gliomas remain incompletely understood. While IDH-mutant gliomas are biologically distinct from their IDH-wildtype counterparts, the spatial dynamics underlying their formation have not been quantified in the molecular era. Identifying where gliomas preferentially arise may help uncover gene expression that contributes to regional vulnerability and gliomagenesis. METHODS We conducted a multi-institutional spatial analysis of 668 adult gliomas: 204 IDH-mutant and 200 IDH-wildtype gliomas from NYU, and 139 IDH-mutant and 125 IDH-wildtype gliomas from the University of Michigan. Tumor volumes were manually segmented, co-registered to MNI space, and localized using the AAL3 brain atlas. Observed tumor frequencies were compared to expected distributions based on regional brain volume. We also analyzed cortical gene expression using publicly available transcriptomic data from the Allen Human Brain Atlas. RESULTS: IDH-mutant gliomas showed a striking predilection for the superior frontal gyrus (SFG), present in 81/204 (39.7%) NYU cases—6.2 times more frequent than in IDH-wildtype gliomas and 3.5 times more than expected based on regional brain volume (p<0.001). IDH-mutant tumor frequency increased progressively from the inferior frontal gyrus (8/204; 3.9%) to the middle frontal gyrus (22/204; 10.8%), peaking in the SFG. These gradients were replicated in the Michigan cohort and conserved across astrocytoma and oligodendroglioma subtypes. By contrast, IDH-mutant gliomas were rare in the occipital lobe, with only 1/204 cases (0.5%)—over tenfold fewer than expected (observed:expected ratio 0.09; p < 0.001). Notably, expression of NLGN3—a synaptic adhesion molecule known to drive glioma progression—was lowest in the inferior frontal gyrus and increased to peak in superior frontal regions, mirroring the tumor distribution. CONCLUSION This large-scale spatial analysis reveals a reproducible, genotype-specific topography of glioma formation. Our findings support a model of regionally constrained gliomagenesis shaped by local gene expression, with implications for future research in cancer neuroscience and tumor–microenvironment interactions.
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Weiss et al. (2025) studied this question.
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