1. Molecular Pathogenesis of Low-Grade Glioma
Devin Bready, BS, Dimitris G. Placantonakis, MD, PhD 
Neurosurgery Clinics 
Volume 30, Issue 1, Pages (January 2019)
DOI: /j.nec
Copyright © 2018 The Author(s) Terms and Conditions

2. Fig. 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 × original magnification × 20. (B) Analysis of genetic profile of IDH1 mutant LGGs in the TCGA. LGAs 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 codeletion seen in oligodendrogliomas.
Neurosurgery Clinics  , 17-25DOI: ( /j.nec )
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3. Fig. 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. Me, Methyl Group.
Neurosurgery Clinics  , 17-25DOI: ( /j.nec )
Copyright © 2018 The Author(s) Terms and Conditions

4. Fig. 3
Effects of mutant IDH on differentiation, telomere elongation, and brain invasion. (A) Although normal hNSCs can be directed to differentiate to neurons and astrocytes (left) as shown by strong Neuron-specific Class III β -tubulin (TUJ1) staining or Glial Fibrillary Acidic Protein (GFAP) staining respectively, hNSCs with 3 genetic alterations found in LGA (3 hits) show a differentiation block as evidenced by the lack of TUJ1 staining or GFAP staining (right). (B) At 63× magnification the nuclei of hNSCs with 3 hits demonstrate foci in which staining for PML and TRF1 colocalize (yellow), indicating ALT, whereas normal hNSCs do not. (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):1271; with permission.)
Neurosurgery Clinics  , 17-25DOI: ( /j.nec )
Copyright © 2018 The Author(s) Terms and Conditions

5. Fig. 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 down-regulated in 3-hit versus normal hNSCs. (B) Similar to the authors’ hNSC model, actual mutant IDH1 LGA tumors show reduced SOX2 × original magnification × 40 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.)
Neurosurgery Clinics  , 17-25DOI: ( /j.nec )
Copyright © 2018 The Author(s) Terms and Conditions