IDH Mutations in Human Glioma

A novel mutation of isocitrate dehydrogenase-1 (IDH1) was recently found in a large percentage of secondary human gliomas. Unlike previously discovered prognostic molecular characteristics, IDH1 mutations were found across gliomas of many different grades and histologies. Further studies have illuminated its utility as a prognostic marker in low-grade and high-grade gliomas and its ability to aid the differentiation and diagnosis of various tumors with histologic ambiguity. As a metabolic enzyme, its inhibitory actions and neomorphic activity present a unique avenue in the understanding of these tumors and potentially a novel mechanism through which they may be treated.

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Isocitrate dehydrogenase-1 (IDH1) mutations are highly conserved to R132 within the enzyme’s active site, suggesting that the mutation may have an oncogenic gain of function.
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IDH1 mutations are associated with other prognostically favorable alterations ( TP53 mutations and 1p19q codeletions) and certain gene cluster profiles (proneural).
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IDH1 mutations are found across different molecular and histologic brain tumor subtypes, suggesting they are early genetic alterations in tumorigenesis.
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Novel IDH1 sequencing and staining techniques have allowed this marker to play an increasingly important role in the histologic determination of brain tumor specimens.

Key points

Introduction

The classification of human brain tumors by the World Health Organization (WHO) scale based on tumor histology remains the gold standard in the diagnosis and prognosis of glioma. In addition to the traditional microscopic characteristics that subcategorize these tumor classes, mounting evidence has come to support distinct genetic aberrations associated with individual tumor sets within this grading scheme. For example, mutations in TP53 are commonly found in astrocytomas (50%–90%) and oligoastrocytomas (40%–50%) but are infrequent in oligodendrogliomas (5%–10%). On the other hand, 1p19q deletions are frequent in oligodendrogliomas (50%–70%) and less common to rare in oligoastrocytomas (30%–50%) and astrocytomas (0%–15%). Although both TP53 mutations and 1p19q codeletions have been associated with improved prognosis, these mutations are mutually exclusive in gliomas, providing molecular evidence to support the histologic stratification of these tumors.

Recently, a sentinel paper by Parsons and colleagues demonstrated the existence of a novel glioma-associated mutation in isocitrate dehydrogenase-1 (IDH1) in 12% of patients with glioblastoma (GBM) via high-throughput gene expression analysis of 20,661 protein coding genes. IDH1 is 1 of 3 metabolic enzymes (along with IDH2 and IDH3) that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) while reducing NADP ⁺to NADPH (NAD ⁺to NADH in the case of IDH3). Mutations in IDH1 were found to be associated with younger age, secondary GBMs (grade IV tumors that arise from biopsy-proven lower-grade predecessors), and increased overall survival (OS). Subsequently, a multitude of retrospective and prospective studies have emerged investigating the frequency, function, and prognostic utility of this mutation in human glioma.

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