Glioma epigenetics: From subclassification to novel treatment options

Gusyatiner, Olga; Hegi, Monika E.

doi:10.1016/j.semcancer.2017.11.010

Cited by 424 publications

(332 citation statements)

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“…1,2 World Health Organization's updated classification of central nervous system tumors in 2016 insists that the standard diagnostic evaluation of low-grade gliomas should now include a molecular assessment of the genes involved, like the mutations of isocitrate dehydrogenases (IDHs) IDH1 and IDH2 and p53 protein. 3,4 The IDH catalyzes the conversion of isocitrate to alphaketoglutarate (KG). The IDH is present in 3 isoforms: IDH1 located in the cytoplasm, IDH2 located in the mitochondria, and IDH3 which is part of the tricarboxylic acid cycle.…”

Section: Introductionmentioning

confidence: 99%

“…The IDH is present in 3 isoforms: IDH1 located in the cytoplasm, IDH2 located in the mitochondria, and IDH3 which is part of the tricarboxylic acid cycle. 4 Patients with low-grade gliomas including astrocytomas and oligodendrogliomas are characterized by mutations in the active site of IDH1 at position R132 and IDH2 at position R172. In the mutated case, both IDH1 and IDH2 catalyze the conversion of alpha-KG to beta-hydroxyglutarate (2-HG); supernormal levels of intracellular 2-HG result in hypermethylation of target genes such as TET2 involved in cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

“…In the mutated case, both IDH1 and IDH2 catalyze the conversion of alpha-KG to beta-hydroxyglutarate (2-HG); supernormal levels of intracellular 2-HG result in hypermethylation of target genes such as TET2 involved in cell differentiation. 4 The wildtype TP53 gene has an indispensable role in several cellular 2 Cancer Informatics processes, including tumor suppression, apoptosis, DNA repair, autophagy, and so on, but is often mutated or deleted at the early stage of low-grade gliomas. In about 30% to 40% of cases of astrocytomas, a loss of p53 function can be observed at an early stage.…”

Section: Introductionmentioning

confidence: 99%

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Computational Analysis of IDH1, IDH2, and TP53 Mutations in Low-Grade Gliomas Including Oligodendrogliomas and Astrocytomas

et al. 2020

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Introduction: The emergence of new omics approaches, such as genomic algorithms to identify tumor mutations and molecular modeling tools to predict the three-dimensional structure of proteins, has facilitated the understanding of the dynamic mechanisms involved in the pathogenesis of low-grade gliomas including oligodendrogliomas and astrocytomas. Methods: In this study, we targeted known mutations involved in low-grade gliomas, starting with the sequencing of genomic regions encompassing exon 4 of isocitrate dehydrogenase 1 ( IDH1) and isocitrate dehydrogenase 2 ( IDH2) and the four exons (5-6 and 7-8) of TP53 from 32 samples, followed by computational analysis to study the impact of these mutations on the structure and function of 3 proteins IDH1, IDH2, and p53. Results: We obtain a mutation that has an effect on the catalytic site of the protein IDH1 as R132H and on the catalytic site of the protein IDH2 as R172M. Other mutations at p53 have been identified as K305N, which is a pathogenic mutation; R175 H, which is a benign mutation; and R158G, which disrupts the structural conformation of the tumor suppressor protein. Conclusion: In low-grade gliomas, mutations in IDH1, IDH2, and TP53 may be the key to tumor progression because they have an effect on the function of the protein such as mutations R132H in IDH1 and R172M in IDH2, which change the function of the enzyme alpha-ketoglutarate, or R158G in TP53, which affects the structure of the generated protein, thus their importance in understanding gliomagenesis and for more accurate diagnosis complementary to the anatomical pathology tests.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Computational Analysis of IDH1, IDH2, and TP53 Mutations in Low-Grade Gliomas Including Oligodendrogliomas and Astrocytomas

et al. 2020

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“…Glioma constitutes over 70% of primary malignant tumor of the central nervous system (CNS) (Gusyatiner & Hegi, 2018). Glioblastoma remains the most aggressive and highly invasive type of glioma, representing approximately 14.9% of all CNS tumors and 46.6% of all primary malignant brain tumors (Ostrom et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Restructuring of contralateral gray matter volume associated with cognition in patients with unilateral temporal lobe glioma before and after surgery

Yang

et al. 2019

Human Brain Mapping

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Glioma can cause variable alterations to the structure and function of the brain. However, there is a paucity of studies on the gray matter (GM) volume alterations in the brain region opposite the temporal glioma before and after surgery. Therefore, the present study was initiated to investigate the alternation in contralateral homotopic GM volume in patients with unilateral temporal lobe glioma and further, assess the relationship between GM volume alternations with cognition. Eight left temporal lobe glioma patients (LTPs), nine right temporal lobe glioma patients (RTPs), and 28 demographically matched healthy controls (HCs) were included. Using voxel‐based morphometry method, alternations in the contralateral homotopic GM volume in patients with unilateral temporal lobe glioma was determined. Furthermore, the correlation analysis was performed to explore the relationship between cognitive function and altered GM volume. In the preoperative analysis, compared to HCs, LTPs exhibited increased GM volume in right inferior temporal gyrus and right temporal pole (superior temporal gyrus), and, RTPs presented increased GM volume in left inferior temporal gyrus. In the postoperative analysis, compared to HCs, RTPs presented increased GM volume in left middle temporal gyrus. Furthermore, the increased GM volume was significantly positively correlated with the memory test but negatively correlated with the visuospatial test. This study preliminarily confirmed that there were compensatory changes in the GM volume in the contralateral temporal lobe in unilateral temporal lobe glioma patients. Furthermore, alterations of GM volume may be a mechanism for cognitive function compensation.

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“…Epigenetic regulator plays important roles in GBM progression. [5][6][7] MYST1, also termed as KAT8, MOZ, YBF2, SAS2, MOF, or TIP60 protein 1, is a kind of histone acetylation enzyme belonging to the MYST family and contains a chromodomain, a zinc finger motif, and a HAT domain. 8,9 As a catalytic subunit, MYST1 forms two distinct multiprotein complexes, MSL and NSL, which acetylates H4K16 as well as H4K5 and H4K8.…”

Section: Introductionmentioning

confidence: 99%

MYST1/KAT8 contributes to tumor progression by activating EGFR signaling in glioblastoma cells

Dong

Zou

et al. 2019

Cancer Medicine

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With short survival time, glioblastoma (GBM) is the most malignant tumor in the central nervous system. Recently, epigenetic enzymes play essential roles in the regulation of tumorigenesis and cancer development of GBM. However, little is known about MYST1/KAT8/MOF, a histone acetylation enzyme, in GBM. The present study shows that MYST1 promotes GBM progression through activating epidermal growth factor receptor (EGFR) signaling. MYST1 expression was increased in GBM and was negatively correlated with prognosis in patients with glioma and GBM. Knockdown of MYST1 reduced cell proliferation and BrdU incorporation in LN229, U87, and A172 GBM cells. Besides, MYST1 downregulation also induced cell cycle arrest at G2M phase, as well as the reduced expression of CDK1, Cyclin A, Cyclin B1, and increased expression of p21CIP1/Waf1. Meanwhile, Self‐renewal capability in vitro and tumorigenecity in vivo were also impaired after MYST1 knockdown. Importantly, MYST1 expression was lowly expressed in mesenchymal subtype of GBM and was positively correlated with EGFR expression in a cohort from The Cancer Genome Atlas. Western blot subsequently confirmed that phosphorylation and activation of p‐Try1068 of EGFR, p‐Ser473 of AKT and p‐Thr202/Tyr204 of Erk1/2 were also decreased by MYST1 knockdown. Consistent with the results above, overexpression of MYST1 promoted GBM growth and activated EGFR signaling in vitro and in vivo. In addition, erlotinib, a US Food and Drug Administration approved cancer drug which targets EGFR, was able to rescue MYST1‐promoted cell proliferation and EGFR signaling pathway. Furthermore, the transcription of EGF, an EFGR ligand, was shown to be positively regulated by MYST1 possibly via H4K16 acetylation. Our findings elucidate MYST1 as a tumor promoter in GBM and an EGFR activator, and may be a potential drug target for GBM treatment.

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Glioma epigenetics: From subclassification to novel treatment options

Cited by 424 publications

References 100 publications

Computational Analysis of IDH1, IDH2, and TP53 Mutations in Low-Grade Gliomas Including Oligodendrogliomas and Astrocytomas

Computational Analysis of IDH1, IDH2, and TP53 Mutations in Low-Grade Gliomas Including Oligodendrogliomas and Astrocytomas

Restructuring of contralateral gray matter volume associated with cognition in patients with unilateral temporal lobe glioma before and after surgery

MYST1/KAT8 contributes to tumor progression by activating EGFR signaling in glioblastoma cells

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