Molecular Pathogenesis of Low-Grade Glioma

Abstract

Advances in genome sequencing have elucidated the genetics of low-grade glioma. Available evidence indicates a neomorphic mutation in isocitrate dehydrogenase (IDH) initiates gliomagenesis. Mutant IDH produces the oncometabolite 2-hydroxyglutarate, which inhibits enzymes that demethylate genomic DNA and histones. Recent findings by the authors and others suggest the ensuing hypermethylation alters chromatin conformation and the transcription factor landscape in brain progenitor cells, leading to a block in differentiation and tumor initiation. Work in preclinical models has identified selective metabolic and molecular vulnerabilities of low-grade glioma. These new concepts will trigger a wave of innovative clinical trials in the near future.

Keywords: Astrocytoma; Low-grade glioma; Mutant IDH; Oligodendroglioma.

Figure 1.. Radiographic and histologic features of LGG.

A. The MRI shows a patient with a large, brain-infiltrating IDH mutant astrocytoma. At the histologic level, tumor cells were positive for the R132H IDH1 mutation; P53 nuclear staining, suggesting loss-of-function mutation; and loss of ATRX. H&E: hematoxylin and eosin staining. B. Analysis of genetic profile of IDH1 mutant LGGs in the TCGA. Low-grade astrocytomas (LGA) and oligodendrogliomas (oligo) have mutually exclusive genetic changes. LGAs are characterized by loss-of-function TP53 and ATRX mutations, and do not show the 1p/19q co-deletion seen in oligodendrogliomas.

Figure 2.. Metabolic and epigenetic effects of mutant IDH.

A. IDH’s normal role is the production of α-KG, a metabolic intermediate necessary for catalytic activity of enzymes that include Ten-Eleven Translocases (TET), which initiate DNA demethylation, and Jumonji histone demethylases. B. The oncogenic production of 2HG directly inhibits such enzymes, leading to DNA and histone hypermethylation.

Figure 3.. Effects of mutant IDH on differentiation, telomere elongation and brain invasion.

A. While normal hNSCs can be directed to differentiate to neurons and astrocytes (left), hNSCs with the 3 genetic alterations found in LGA (3 hits) show a differentiation block (right). B. Nuclei of hNSCs with the 3 hits demonstrate foci in which PML and TRF1 co-localize (yellow), indicating ALT. C. Injection of normal or 3-hit hNSCs expressing the fluorescent protein mCherry into the brain of immunosuppressed (NOD.SCID) mice reveals a significant increase in brain invasion by 3-hit cells. The dotted lines outline the injection tracks. In all images, nuclei were counterstained with DAPI. Adapted from Modrek AS, Golub D, Khan T, et al. Low-grade astrocytoma mutations in IDH1, P53, and ATRX cooperate to block differentiation of human neural stem cells via repression of SOX2. Cell Rep. 2017;21(5):1267–80; with permission.

Figure 4.. Mutant IDH alters chromatin conformation in LGA initiation.

A. Confocal microscopic images of hNSCs expressing mCherry injected in the mouse brain. The expression of transcription factor SOX2 is downregulated in 3-hit vs. normal hNSCs. B. Similar to our hNSC model, actual mutant IDH1 LGA tumors show reduced SOX2 expression relative to native neural progenitor cells in the subventricular zone of the normal adult brain. C. Schematic illustrating how methylation of CTCF motifs due to mutant IDH alters chromatin conformation, leading to disassociation of SOX2 promoter from an enhancer and reduced SOX2 transcription. In all images, nuclei were counterstained with DAPI. Adapted from Modrek AS, Golub D, Khan T, et al. Low-grade astrocytoma mutations in IDH1, P53, and ATRX cooperate to block differentiation of human neural stem cells via repression of SOX2. Cell Rep. 2017;21(5):1267–80; with permission.