Genetic, cellular, and connectomic characterization of the brain regions commonly plagued by glioma

Abstract

For decades, it has been known that gliomas follow a non-random spatial distribution, appearing more often in some brain regions (e.g. the insula) compared to others (e.g. the occipital lobe). A better understanding of the localization patterns of gliomas could provide clues to the origins of these types of tumours, and consequently inform treatment targets. Following hypotheses derived from prior research into neuropsychiatric disease and cancer, gliomas may be expected to localize to brain regions characterized by functional hubness, stem-like cells, and transcription of genetic drivers of gliomagenesis. We combined neuroimaging data from 335 adult patients with high- and low-grade glioma to form a replicable tumour frequency map. Using this map, we demonstrated that glioma frequency is elevated in association cortex and correlated with multiple graph-theoretical metrics of high functional connectedness. Brain regions populated with putative cells of origin for glioma, neural stem cells and oligodendrocyte precursor cells, exhibited a high glioma frequency. Leveraging a human brain atlas of post-mortem gene expression, we found that gliomas were localized to brain regions enriched with expression of genes associated with chromatin organization and synaptic signalling. A set of glioma proto-oncogenes was enriched among the transcriptomic correlates of glioma distribution. Finally, a regression model incorporating connectomic, cellular, and genetic factors explained 58% of the variance in glioma frequency. These results add to previous literature reporting the vulnerability of hub regions to neurological disease, as well as provide support for cancer stem cell theories of glioma. Our findings illustrate how factors of diverse scale, from genetic to connectomic, can independently influence the anatomic localization of brain dysfunction.

Lesion covariance networks reveal proposed origins and pathways of diffuse gliomas

“…Our findings contribute to this literature by illustrating, in human patients, that glioma localization follows intrinsic functional and structural connectivity networks. This result is consistent with prior work from our group demonstrating that gliomas localize to functional brain hubs (Mandal et al, 2020).…”

“…In contrast to early ideas that gliomas originate from mature glial cells in the same locations where they are observed, current theories imply that tumors originate from neurogenic niches in the subventricular zone (SVZ), from which they then migrate to populate distributed brain areas (Jiang and Uhrbom, 2012;Lee et al, 2018;Sanai et al, 2005). This idea is supported by genomic evidence from patients (Lee et al, 2018) as well as the observation of significantly elevated glioma frequency surrounding neurogenic niches (Mandal et al, 2020). In parallel, other research has indicated that glioma stem cells travel along previously healthy brain structures, including blood vessels and white matter tracts, suggesting that large-scale connectivity networks may help describe glioma migration (Cuddapah et al, 2014;Gillespie and Monje, 2018).…”

BOLD Coupling between Lesioned and Healthy Brain Is Associated with Glioma Patients’ Recovery

“…Although the origin of glioma is still a matter of debate, it has been hypothesised that oligodendrocyte precursor cells (OPCs) are the cellular source of this type of tumour [ 52 ], which is supported by the fact that gliomas can be transformed into cancer cells through experimental manipulation [ 53 ]. We have recently shown that glioma incidence is higher in regions populated by OPCs, such as the temporal and frontal cortices [ 29 ]. On the contrary, excitatory and inhibitory neurons, which are directly associated with the GS [ 11 ], show a different distribution pattern, with decreased populations in medial temporal and frontal cortices [ 54 ].…”

“…Thus, the negative correlation between tumour incidence and regional coupling with the GS may reflect the differential cell organisation of the underlying tissue. Alternatively, but not mutually exclusively, we have also shown that glioma incidence is higher in regions with high functional connectedness regardless of tumour grade [ 29 ]. This preferential tumour localisation follows intrinsic functional connectivity networks, possibly reflecting tumour cell migration along neuronal networks that support glioma cell proliferation [ 55 ].…”

“…Second, there were structural MRI data and tumour masks of 335 patients with glioma (no fMRI available) from the Multimodal Brain Tumour Image Segmentation Challenge 2019 (BraTS; , accessed on 30 June 2019). Pre-processing and tumour frequency estimation are described in [ 29 ]. The following processing and analyses steps refer exclusively to data from 17 patients with diffuse glioma.…”