IDH1 and IDH2 Mutations in Gliomas

By Frank M. Sacks. New England Journal of Medicine, 2009

3,049 citations recorded by the source corpus.

BACKGROUND A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). METHODS We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. RESULTS We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein. CONCLUSIONS Mutations of NADP+-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.

Subfields: Cell Biology, Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/e1a23654a699c01a9e17af5aaf8077c712f8802d

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Links between metabolism and cancer. (2012, background): “More recently, mutations in IDH stemming from cancer genome sequencing efforts uncovered remarkable connections between a mutant metabolic enzyme and tumorigenesis (Parsons et al. 2008; Yan et al. 2009).”
Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations (2010, background): “…has revealed that this mutation is present in a high proportion of gliomas and secondary glioblastomas, but not in other human malignancies (Balss et al., 2008; Bleeker et al., 2009; Hartmann et al., 2009; Kang et al., 2009; Sanson et al., 2009; Watanabe et al., 2009; Yan et al., 2009).”
Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation (2010, background): “Although mutations in IDH1 and IDH2 are thought to be mutually exclusive based on mutational studies in malignant gliomas (Hartmann et al., 2009; Yan et al., 2009), occasional rare AML patients have been reported with concurrent mutations in both IDH1 and IDH2 (Paschka et al., 2010).”
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New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs (2016, neutral): “…aberrations in high-grade pediatric CNS tumors (Capper et al., 2010; Chan et al., 2013; Hasselblatt et al., 2013; Margol and Judkins, 2014; Pajtler et al., 2015; Parker et al., 2014; Schneppenheim et al., 2010; Schwartzentruber et al., 2012; Venneti et al., 2013; Wu et al., 2012; Yan et al., 2009).”