Detection of oncogenic IDH1 mutations using magnetic resonance spectroscopy of 2-hydroxyglutarate

Andronesi, Ovidiu C.; Rapalino, Otto; Gerstner, Elizabeth R.; Chi, Andrew; Batchelor, Tracy T.; Cahill, Daniel P.; Sorensen, A. Gregory; Rosen, Bruce R.

doi:10.1172/jci67229

Cited by 157 publications

(101 citation statements)

References 58 publications

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“…Obtaining tumor tissue from patients with glioma for diagnosticandmolecularanalysis requires invasiveneurosurgical procedures, and a noninvasive means to detect 2-HG, a potential surrogate biomarker for IDH mutation, could serve as a valuable aid in diagnosis, prognostication, and, potentially, assessment of therapeutic response. Noninvasive methods such as imaging methods to detect and quantify 2-HG levels in glioma tumors are already under investigation [37,38]. Furthermore, evidence is emerging that patients with IDH-mutant glioma survive longer with greater extent of resection at diagnosis [39]; therefore, knowledge of whether a tumor harbors a IDH mutation before surgery may impact therapeutic decisions and survival.…”

Section: Discussionmentioning

confidence: 99%

Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma

et al. 2016

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Background. Recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, which are frequent in gliomas, result in marked accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG) within tumors. In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments. Circulating 2-HG in patients with glial malignancies has not been thoroughly investigated. Methods. In this study, we analyzed 2-HG levels in the serum and urine of a large set of patients with IDH-mutant and IDHwild-type glioma, and the cerebrospinal fluid (CSF) from a subset of this cohort.

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Section: Discussionmentioning

confidence: 99%

Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma

et al. 2016

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“…However, up to the time of preparation for this manuscript, elevations in serum and urine 2-HG have not been reported in IDH-mutant solid tumors. Levels of intratumoral 2-HG have been shown to be elevated in IDH1-mutant glioma tissue [18,31] using both in vitro and in vivo techniques [32,33]. Nevertheless, an earlier small study of IDH1-mutant gliomas failed to detect an elevation in circulating 2-HG levels in sera of affected patients [34].…”

Section: Discussionmentioning

confidence: 99%

Isocitrate Dehydrogenase 1 (IDH1) Mutation in Breast Adenocarcinoma Is Associated With Elevated Levels of Serum and Urine 2-Hydroxyglutarate

et al. 2014

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Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in these malignancies. We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR1) breast adenocarcinoma. This patient was initially treated for locally advanced disease, but then suffered a relapse and metastasis, at which point an IDH1-R132 mutation was discovered in an affected lymph node. The mutation was subsequently found in the primary tumor tissue and all metastatic sites, but not in an uninvolved lymph node. In addition, the patient's serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR1 breast carcinoma whose tumors were found to harbor wild-type IDH1. In summary, IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma. This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme. The Oncologist 2014; 19:602-607 Implications for Practice: Isocitrate dehydrogenase (IDH) mutations have been identified in various hematologic and solid-tumor malignancies. To date, there are no published reports of these mutations in breast cancer. With this article, we describe a case of hormone receptor-positive adenocarcinoma of the breast with an IDH1 (p.R132L) mutation. The impacted patient had markedly elevated levels of serum and urine 2-hydroxyglutarate, an oncometabolite that accumulates as a result of the neomorphic activity of the altered IDH enzyme. IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma, and these findings may carry future therapeutic implications, given the emergence of targeted therapies against the altered IDH protein.

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“…20 This study used a liquid chromatography/mass spectrometry metabolomics approach to discover that IDH1-R132H mutant proteins acquire a neomorphic function that leads to the production of high levels of the "R" enantiomer of 2-hydroxyglutarate (2-HG) that are never seen at comparable levels in an IDH1 wild-type setting and can be detected using MR spectroscopy. 2 Because tumor cells typically harbor one copy of IDH1 mutation and do not exhibit loss of heterozygosity at that locus, these mutations are likely gain of function in nature. Significant effort is underway to understand the mechanistic underpinnings of the IDH1 mutant state.…”

Section: The Idh1 Story: Not All Gliomas Are Created Equalmentioning

confidence: 99%

Molecular and cellular heterogeneity: the hallmark of glioblastoma

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Kim

Beaumont

et al. 2014

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172

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There has been increasing awareness that glioblastoma, which may seem histopathologically similar across many tumors, actually represents a group of molecularly distinct tumors. Emerging evidence suggests that cells even within the same tumor exhibit wide-ranging molecular diversity. Parallel to the discoveries of molecular heterogeneity among tumors and their individual cells, intense investigation of the cellular biology of glioblastoma has revealed that not all cancer cells within a given tumor behave the same. The identification of a subpopulation of brain tumor cells termed “glioblastoma cancer stem cells” or “tumor-initiating cells” has implications for the management of glioblastoma. This focused review will therefore summarize emerging concepts on the molecular and cellular heterogeneity of glioblastoma and emphasize that we should begin to consider each individual glioblastoma to be an ensemble of molecularly distinct subclones that reflect a spectrum of dynamic cell states.

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Detection of oncogenic IDH1 mutations using magnetic resonance spectroscopy of 2-hydroxyglutarate

Cited by 157 publications

References 58 publications

Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma

Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma

Isocitrate Dehydrogenase 1 (IDH1) Mutation in Breast Adenocarcinoma Is Associated With Elevated Levels of Serum and Urine 2-Hydroxyglutarate

Molecular and cellular heterogeneity: the hallmark of glioblastoma

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