IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas

Ichimura, Koichi; Pearson, Danita M.; Kocialkowski, Sylvia; Bäcklund, L. Magnus; Chan, Raymond; Jones, David; Collins, V. Peter

doi:10.1215/15228517-2009-025

Cited by 521 publications

(497 citation statements)

References 21 publications

(29 reference statements)

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“…Co-deletion of 1p and 19q is most commonly associated with oligodendroglial tumors [8,9] and is both predictive of therapeutic response and prognostic for survival [10,11]. IDH mutations, which are known to be a driver mutation in low-grade gliomas [12,13], are associated with more favorable outcomes as they are known to be more sensitive to chemoradiation [14,15].…”

Section: Introductionmentioning

confidence: 99%

Perfusion and diffusion MRI signatures in histologic and genetic subtypes of WHO grade II–III diffuse gliomas

et al. 2017

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Section: Introductionmentioning

confidence: 99%

Perfusion and diffusion MRI signatures in histologic and genetic subtypes of WHO grade II–III diffuse gliomas

et al. 2017

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“…Some authors observed that OS and PFS in IDH mutated cases were about twice longer than in wild‐type patients (Arita et al., 2015; Polivka et al., 2014), and others showed that mutation in IDH1 was an independent factor for a favorable prognosis (Brennan et al., 2013; Ducray et al., 2011; Polivka et al., 2014; Sanson et al., 2009; Shibahara et al., 2011). However, this hypothesis was rejected by other groups taking into account other factors such as surgery and radiotherapy‐chemotherapy treatments when evaluating the survival of these patients (Ichimura et al., 2009; Rineer et al., 2010; Thota et al., 2012). In this Spanish population, patients with primary tumors harboring R132H mutation had a relative but not significant reduction in death risk of 65% compared with the wild‐type patients, and none of these IDH1 R132H heterozygote patients progressed, conferring this alteration with a significant PFS advantage.…”

Section: Discussionmentioning

confidence: 99%

Genetic alterations of IDH1 and Vegf in brain tumors

et al. 2017

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BackgroundThis study evaluates the presence of R132H mutation in isocitrate dehydrogenase (IDH1) gene and the vascular endothelial growth factor (VEGF) +936 C/T polymorphism in brain tumors. The impact of these genetic alterations on overall survival (OS) and progression free survival (PFS) was evaluated.MethodsA cohort of 80 patients surgically treated at Hospital Clínico San Carlos, Madrid, between March 2004 and November 2012, was analyzed. Tumors were distributed in 73 primary brain tumors (gliomas, meningiomas, hemangiopericytomas and hemangioblastomas) and seven secondary tumors evolved from a low grade glioma, thus providing a mixed sample.Results IDH1 R132H gene mutation was found in 12 patients (15%) and appears more frequently in secondary tumors (5 (71.4%) whereas in 7 (9.7%) primary tumors (p < .001)). The mutation is related to WHO grade II in primary tumors and a supratentorial location in secondary tumors. The OS analysis for IDH1 showed a tendency towards a better prognosis of the tumors containing the mutation (p = .059).The IDH1 R132H mutation confers a better PFS (p = .025) on primary tumors. The T allele of VEFG +936 C/T polymorphism was found in 16 patients (20%). No relation was found between this polymorphism and primary or secondary tumor, neither with OS or PFS.Conclusions IDH1 R132H gene mutation is exclusive in supratentorial tumors and more frequent in secondary ones, with a greater survival trend and better PFS in patients who carry it. The T allele of VEGF +936 C/T polymorphism is more common in primary tumors, although there is no statistical relation with survival.

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“…10 In fact, co-expression of wildtype IDH1 with the mutant protein (as is the case in most IDH1-mutated gliomas) may enhance 2HG production, as wild-type IDH1 activity increases levels of NADPH and aKG, both necessary substrates for neomorphic production of 2HG. 10 LOH of the IDH1 locus is very uncommon in gliomas, 29 while homozygous IDH1 mutations in AML are very rare, 26 and whether the clinical behavior of these tumors is distinct from those with typical IDH mutations is not known.…”

Section: Discussionmentioning

confidence: 99%

Expanding the spectrum of IDH1 mutations in gliomas

Gupta

Flanagan

et al. 2013

Modern Pathology

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Mutations in isocitrate dehydrogenase -1 or -2 (IDH1 or IDH2) are found in the majority of WHO grade II and III diffuse gliomas and secondary glioblastomas. IDH mutation screening is rapidly becoming part of the routine pathological work up of human brain tumors, providing both diagnostic and prognostic information. Here, we characterize four rare and novel IDH1 mutations identified in surgical human glioma samples: two instances of an IDH1 p.R132S mutation caused by a previously undescribed dinucleotide deletion/insertion mutation, a novel homozygous somatic IDH1 p.R132L mutation, and an IDH1 p.R100Q mutation. Characterization of novel and rare IDH mutations may provide additional insight into the mechanisms of mutant IDH in neoplasia. Keywords: brain tumor; glioma; IDH; isocitrate dehydrogenase; mutation testing IDH1 and IDH2 mutations were first identified during exome-wide sequencing of glioblastomas in 2008, 1 occurring predominantly in those that had arisen through progression of a lower grade glioma (ie, secondary glioblastomas). Subsequently, IDH mutations have been described in 70-80% of grade II and III astrocytomas, oligodendrogliomas and secondary glioblastomas, but are rare or nonexistent in other brain tumors. 2 IDH mutations tend to occur in younger individuals and carry significant prognostic significance, in that those with IDHmutant tumors have longer disease-free survival and show better response to treatment. 3-5 For these reasons, assessment of IDH mutation status has rapidly become incorporated as a standard component in the neuropathological assessment of brain tumors. 6 IDH mutations in gliomas are largely known to be heterozygous missense mutations in codon R132 of IDH1, or much less commonly, the synonymous codon (R172) of IDH2. These mutations result in substitution of a highly conserved and structurally important arginine residue in the IDH substrate binding site. 2,7 The most common IDH mutation is IDH1 p.R132H, accounting for around 90% of IDHmutant glioma cases; less commonly, the IDH1 R132 substitution is with serine (p.R132S), leucine (p.R132L), glycine (p.R132G), cysteine (p.R132C) or valine (p. R132V) 2,8 and, at the molecular level, all but one of the reported cases are due to singlenucleotide substitutions. Mutations of IDH2 are relatively rare, accounting for B3-5% of all described IDH mutations, but they carry similar prognostic implications. 1 Mutations in IDH genes are thought to contribute to neoplasia through a dominant-negative effect on the protein's wild-type function and/or a neomorphic gain of function of the mutant protein. 6 Downstream effects of mutant IDH include decreased cellular NADPH and alpha-ketoglutarate (aKG) levels, 9 HIF1a stabilization, 9 and increased production of 2-hydroxyglutarate (2HG), 10 which competitively inhibits aKG-dependant enzymes such as histone methyltransferases and 5-methylcytosine hydroxylases. 11 Homozygous mutations of IDH1 or IDH2 in gliomas have not been described, arguing against a simple loss of function mechanism.

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IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas

Cited by 521 publications

References 21 publications

Perfusion and diffusion MRI signatures in histologic and genetic subtypes of WHO grade II–III diffuse gliomas

Perfusion and diffusion MRI signatures in histologic and genetic subtypes of WHO grade II–III diffuse gliomas

Genetic alterations of IDH1 and Vegf in brain tumors

Expanding the spectrum of IDH1 mutations in gliomas

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