Lesion covariance networks reveal proposed origins and pathways of diffuse gliomas

Diffuse gliomas have been hypothesized to originate from neural stem cells in the subventricular zone. Here, we evaluated this hypothesis by mapping independent sources of glioma localization and determining their relationships with neurogenic niches, genetic markers, and large-scale connectivity networks. Using lesion data from a total of 410 patients with glioma, we identified -- and replicated in an independent sample -- three lesion covariance networks (LCNs), which reflect clusters of frequent glioma co-localization. Each LCN overlapped with a distinct horn of the lateral ventricles. The first LCN, which overlapped with the anterior horn, was associated with low-grade, IDH-mutated/1p19q-codeleted tumors, as well as a neural transcriptomic signature and improved overall survival. Each LCN significantly corresponded with multiple brain networks, with LCN1 bearing an especially strong relationship with structural and functional connectivity, consistent with its neural transcriptomic profile. Finally, we identified subcortical, periventricular structures with functional connectivity patterns to the cortex that significantly matched each LCN. Cumulatively, our findings support a model wherein periventricular brain connectivity guides tumor development.