Biological and Translational Insights of Mutant IDH1/2 in Glioma

Neurosurg Focus 34 (2):E2, 2013 ©AANS, 2013 From genomics to the clinic: biological and translational insights of mutant IDH1/2 in glioma GAVIN P. DUNN, M.D., PH.D.,1 OVIDIU C. ANDRONESI, M.D., PH.D.,2 AND DANIEL P. CAHILL, M.D., PH.D.1 Departments of 1Neurosurgery and 2Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts The characterization of the genomic alterations across all human cancers is changing the way that malignant disease is defined and treated. This paradigm is extending to glioma, where the discovery of recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) gene has shed new light on the molecular landscape in glioma and other IDH- mutant cancers. The IDH1 mutations are present in the vast majority of low-grade gliomas and secondary glioblastomas. Rapidly emerging work on the consequences of mutant IDH1 protein expression suggests that its neomorphic enzymatic activity catalyzing the production of the oncometabolite 2-hydroxyglutarate influences a range of cellular programs that affect the epigenome, transcriptional programs, hypoxia-inducible factor biology, and development. In the brief time since its discovery, knowledge of the IDH mutation status has had significant translational implications, and diagnostic tools are being used to monitor its expression and function. The concept of IDH1-mutant versus IDH1-wild type will become a critical early distinction in diagnostic and treatment algorithms. (http://thejns.org/doi/abs/10.3171/2012.12.FOCUS12355) KEY WORDS • isocitrate dehydrogenase 1 • isocitrate dehydrogenase 2 • glioblastoma • low-grade glioma • magnetic resonance spectroscopy HE comprehensive taxonomic encyclopedia of the significant because there are specific inhibitors that target genetic alterations underlying all cancers is rapidly their expressed proteins and lead to dramatic clinical re- becoming widely available.61,85,91 To date, this mo- sponse in patients with these cancers. Tlecular genomic focus has driven an evolving perspective Several groups have used a similar approach to glio- on malignancies as lesions that are defined by (in addition blastoma, the most common intrinsic brain tumor.59,65 to microscopic histological findings) their signature tu- Extensive characterization of the genomic changes un- mor genome alterations. Indeed, the lingua franca of this derlying these cancers has set the stage for a reevaluation genome-based framework is increasingly pervasive, as of their clinical management. A prototypic example has is exemplified by lesions such as HER2-amplified breast been the recent identification of mutations in the IDH1 cancer,83 BCR-ABL–rearranged chronic myeloid leuke- gene,65 a stunning and unexpected discovery that has led mia,23 EGFR-mutant55 or EML4-ALK–rearranged48 non– to new insights into glioma and cancer biology, has fu- small cell lung cancer, and BRAF-mutant melanoma16 eled new interest in studies of cancer metabolism, and that populate the growing lexicon of molecular oncology. has clear clinical implications. Importantly, the presence of these alterations is clinically Today, neurooncologists and neurosurgeons increasingly stratify glial neoplasms into IDH1-mutant or IDH1- WT disease.24,92 Indeed, the divergent clinical character- Abbreviations used in this paper: a-KG = a-ketoglutarate; AML istics of histopathologically identical primary (IDH1-WT) = acute myeloid leukemia; D-2-HG = D-2-hydroxyglutarate; D-2- and secondary (IDH1-mutant) glioblastomas are lending HGA = D-2-hydroxyglutaric aciduria; G-CIMP = glioma CpG island methylator phenotype; GFAP = glial fibrillary acidic protein; further support to the notion that these tumors represent HIF = hypoxia-inducible factor; IDH1/2 = isocitrate dehydrogenase different diseases. Herein we review the discovery and 1 and 2; LGG = low-grade glioma; MRS = MR spectroscopy; incidence of IDH mutation in glioma and other cancers, NADPH = nicotinamide adenine dinucleotide phosphate (reduced our current understanding of mutant IDH biology, and its form); TCA = tricarboxylic acid; WT = wild type. increasing translational implications. Neurosurg Focus / Volume 34 / February 2013 1 Unauthenticated | Downloaded 10/05/21 10:38 AM UTC G. P. Dunn, O. C. Andronesi, and D. P. Cahill Mutations of IDH1 in Cancer tion in glioblastomas has been followed by significant work from many other groups that together have begun to Discovery of Mutant IDH1 clarify the frequency and distribution of IDH1 mutations In 2008, recurrent mutations in IDH1 were first iden- across all brain tumors, including gliomas and other sub- tified through work by the Vogelstein group analyzing types. Many studies have extensively characterized the the DNA sequence of the protein-coding portions of the incidence of IDH mutations in brain tumors.4,31,33,34,77,99 glioblastoma genome (see Parsons et al.65). In that study, Together, this work has revealed critical themes regarding 23,219 transcripts from 20,661 protein-coding genes in recurrent mutations in IDH1/2 loci in tumors of the CNS: 22 malignant gliomas were analyzed by capillary-based 1) mutations are nearly always hemizygous; 2) mutations Sanger sequencing. Of the 22 tumors examined, 7 were almost always occur at conserved codon sequences en- derived directly from patient tissue, and 15 were derived coding a substitution at the R132 position of the IDH1 from xenografts of human tumors. In this initial so-called protein; 3) IDH1 mutation is most often identified in Discovery set, 5 of 22 tumors carried an identical muta- lower-grade (WHO Grades II and III) astrocytomas and tion of the IDH1 gene that produced the R132H amino oligodendrogliomas rather than primary glioblastomas; acid substitution of the IDH1 protein. Notably, the ages of and 4) only a small number of IDH2 mutations are ob- the patients who harbored this mutation in the Discovery served in brain tumors. The R132H IDH1 mutant is seen set were 30, 31, 32 (2 patients), and 42 years, which is con- in more than 90% of IDH1-mutant tumors, but less com- siderably younger than the historically associated age at mon mutants such as R132C, R132G, R132S, and R132L glioblastoma diagnosis (which is more typically in the 6th have also been identified.31,99 Although the initial discov- or 7th decade of life). Targeted sequencing analysis in a ery of recurrent IDH1 mutations in glioma focused on validation sample set of 127 additional tumors identified glioblastoma, data summarized from a group of studies 13 IDH1 mutations, including 4 (80%) of 5 tumors known show that only approximately 5.6% (75 of 1345) of pri- to be secondary glioblastomas. Parsons et al.65 provided mary glioblastomas are IDH1 mutant4,6,30,33,34,77,96,99 (Table 2 additional important observations that have since been 1). In contrast, more than 76% (94 of 123) of secondary corroborated by other groups. First, the median age of pa- glioblastomas, which are currently defined as Grade IV tients with the IDH1-mutant tumors was 33 years, where- astrocytomas diagnosed in patients with antecedent his- as in the patient group with IDH1-WT tumors, the median tological evidence of a prior lower-grade astrocytoma age was 53 years. Second, patients with IDH1-mutant tu- diagnosis, carry the IDH1 mutation.4,6,33,34,62,77,96,99 In con- mors demonstrated a significantly longer overall survival trast to primary glioblastoma, lower-grade tumors carry a time compared with patients in the IDH1-WT group. high incidence of IDH1 mutations; this gene is mutated in Of the 3 human IDH isoforms, IDH1 is located in the more than 75% of Grade II4,31,33,34,77,96,99 and 62% of Grade cytoplasm and peroxisomes, whereas IDH2 and IDH3 are III gliomas,4,30,31,33,34,77,96,99 approximately 80% of Grade II located within the mitochondria. The IDH proteins are and 70% of Grade III oligodendrogliomas,4,6,31,33,34,77,96,99 known to catalyze the oxidative decarboxylation of isoci- and approximately 80% of Grade II and nearly 70% of trate to a-KG, leading to the production of NADPH in the Grade III oligoastrocytomas.4,31,33,34,77,96,99 Other CNS tu- TCA cycle, a biochemical sequence critical in sugar, lipid, mors found to harbor IDH1 mutations include gangliogli- and amino acid metabolism.70 Prior to the study of Parsons omas, giant cell glioblastomas, and primitive neuroecto- et al., these proteins had not previously been linked to can- dermal tumors, although small numbers of these tumors cer. Although a mutation in IDH1 producing the R132C have been studied.4 substitution had been identified previously in patients with Together, given the high incidence of IDH1 mutation colon cancer, 82 the study of glioblastoma was the first to in LGG and secondary glioblastoma and the compara- demonstrate that IDH1 was recurrently mutated in cancer tively low incidence in primary glioblastoma, it seems and correlated with important clinical parameters. plausible that IDH1-mutant primary glioblastomas may In addition to mutations in IDH1, additional compo- in fact represent misdiagnosed secondary tumors arising nents of the TCA cycle are mutated in other non-CNS from previously undiagnosed LGGs—therefore suggest- cancers. For example, mutations in subunits of the succi- ing that primary glioblastoma should be considered sepa- nate dehydrogenase complex have been identified in para- rately as a purely IDH1-WT disease. gangliomas and pheochromocytomas, and mutations in In contrast to IDH1 mutations, mutations in the IDH2 fumarate hydratase have been associated with renal cell gene are comparatively rare in gliomas. These mutations carcinomas and leiomyomas.39,70 Together with these find- usually confer an amino acid substitution at arginine 172 ings, the growing body of work revealing mutations in of the IDH2 protein. Of 360 primary glioblastomas in genes encoding canonical proteins in metabolism has lent which the IDH2 gene was evaluated, only 1 was found support to Otto Warburg’s nearly century-old hypothesis to harbor a mutation30,99 (Table 1).

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