Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy
Whitney B. Pope,Robert M. Prins,M. Albert Thomas,Rajakumar Nagarajan,Katharine E. Yen,Mark A. Bittinger,Noriko Salamon,Arthur P. Chou,William H. Yong,Horacio Soto,Neil E. Wilson,Edward M. Driggers,Hyun Gyung Jang,Shinsan M. Su,David P. Schenkein,Albert Lai,Timothy F. Cloughesy,Harley I. Kornblum,Hong Wu,Valeria Fantin,Linda M. Liau +20 more
Reads0
Chats0
TLDR
Water-suppressed proton (1H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors.Abstract:
Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(−)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography–mass spectrometry (LC–MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC–MS (r2 = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r2 = 0.59; P = 0.026). In conclusion, water-suppressed proton (1H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.read more
Citations
More filters
Journal ArticleDOI
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
TL;DR: It is argued that altered metabolism has attained the status of a core hallmark of cancer.
Journal ArticleDOI
Metabolic pathways promoting cancer cell survival and growth.
TL;DR: These adaptive mechanisms that promote metabolic reprogramming in cancer and emerging approaches to probe tumour metabolism in vivo are discussed and their potential to expand the metabolic repertoire of malignant cells even further are discussed.
Journal ArticleDOI
Emerging insights into the molecular and cellular basis of glioblastoma
Gavin P. Dunn,Mikael L. Rinne,Mikael L. Rinne,Jill Wykosky,Giannicola Genovese,Steven N. Quayle,Ian F. Dunn,Pankaj K. Agarwalla,Pankaj K. Agarwalla,Milan G. Chheda,Milan G. Chheda,Milan G. Chheda,Benito Campos,Alan Wang,Cameron Brennan,Keith L. Ligon,Frank B. Furnari,Webster K. Cavenee,Ronald A. DePinho,Lynda Chin,William C. Hahn,William C. Hahn +21 more
TL;DR: These studies provide the emerging view that "glioblastoma" represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions.
Journal ArticleDOI
Glutathione levels in human tumors.
TL;DR: Clinical studies in which glutathione was measured in tumor tissue from patients with brain, breast, gastrointestinal, gynecological, head and neck and lung cancer are summarized and approaches that may improve the clinical value of glutATHione as a biomarker are recommended.
Journal ArticleDOI
Glioma Subclassifications and Their Clinical Significance.
TL;DR: This review aims to summarize the current literature regarding glioma subclassifications and their clinical relevance in this evolving field and provides the essential framework for the development and testing of new specific targeted therapies for particular gliomas subtypes.
References
More filters
Journal ArticleDOI
Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1
Roel G.W. Verhaak,Katherine A. Hoadley,Elizabeth Purdom,Victoria Wang,Yuan-yuan Qi,Matthew D. Wilkerson,C. Ryan Miller,Li Ding,Todd R. Golub,Jill P. Mesirov,Gabriele Alexe,Michael S. Lawrence,Michael O'Kelly,Pablo Tamayo,Barbara A. Weir,Stacey Gabriel,Wendy Winckler,Supriya Gupta,Lakshmi Jakkula,Heidi S. Feiler,J. Graeme Hodgson,C. David James,Jann N. Sarkaria,Cameron Brennan,Ari B. Kahn,Paul T. Spellman,Richard K. Wilson,Terence P. Speed,Terence P. Speed,Joe W. Gray,Matthew Meyerson,Gad Getz,Charles M. Perou,Charles M. Perou,D. Neil Hayes +34 more
TL;DR: A robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes is described and multidimensional genomic data is integrated to establish patterns of somatic mutations and DNA copy number.
Journal ArticleDOI
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
D. Williams Parsons,Siân Jones,Xiaosong Zhang,Jimmy Lin,Rebecca J. Leary,Philipp Angenendt,Parminder Mankoo,Hannah Carter,I-Mei Siu,Gary L. Gallia,Alessandro Olivi,Roger E. McLendon,B.K. Ahmed Rasheed,Stephen T. Keir,Tatiana Nikolskaya,Yuri Nikolsky,Dana A. Busam,Hanna Tekleab,Luis A. Diaz,James Hartigan,Doug R. Smith,Robert L. Strausberg,Suely Kazue Nagahashi Marie,Sueli Mieko Oba Shinjo,Hai Yan,Gregory J. Riggins,Darell D. Bigner,Rachel Karchin,Nick Papadopoulos,Giovanni Parmigiani,Bert Vogelstein,Victor E. Velculescu,Kenneth W. Kinzler +32 more
TL;DR: Recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival.
Journal ArticleDOI
IDH1 and IDH2 Mutations in Gliomas
Hai Yan,D. Williams Parsons,Genglin Jin,Roger E. McLendon,B.K. Ahmed Rasheed,Weishi Yuan,Ivan Kos,Ines Batinic-Haberle,Siân Jones,Gregory J. Riggins,Henry S. Friedman,Allan H. Friedman,David A. Reardon,James E. Herndon,Kenneth W. Kinzler,Victor E. Velculescu,Bert Vogelstein,Darell D. Bigner +17 more
TL;DR: Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.
Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1
Roel G.W. Verhaak,Katherine A. Hoadley,Elizabeth Purdom,Victoria Wang,Yuan-yuan Qi,Matthew D. Wilkerson,C. Ryan Miller,Li Ding,Todd R. Golub,Jill P. Mesirov,Gabriele Alexe,Michael S. Lawrence,Michael O'Kelly,Pablo Tamayo,Barbara A. Weir,Stacey Gabriel,Wendy Winckler,Supriya Gupta,Lakshmi Jakkula,Heidi S. Feiler,J. Graeme Hodgson,C. David James,Jann N. Sarkaria,Cameron Brennan,Ari B. Kahn,Paul T. Spellman,Richard K. Wilson,Terence P. Speed,Terence P. Speed,Joe W. Gray,Matthew Meyerson,Gad Getz,Charles M. Perou,Charles M. Perou,D. Neil Hayes +34 more
TL;DR: The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM) and proposed a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes as discussed by the authors.
Journal ArticleDOI
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Lenny Dang,David W. White,Stefan Gross,Bryson D. Bennett,Mark A. Bittinger,Edward M. Driggers,Valeria Fantin,Hyun Gyung Jang,Shengfang Jin,Marie C. Keenan,Kevin Marks,Robert M. Prins,Patrick S. Ward,Katharine E. Yen,Linda M. Liau,Joshua D. Rabinowitz,Lewis C. Cantley,Craig B. Thompson,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Shinsan M. Su +20 more
TL;DR: It is shown that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG), and that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
Related Papers (5)
IDH1 and IDH2 Mutations in Gliomas
Hai Yan,D. Williams Parsons,Genglin Jin,Roger E. McLendon,B.K. Ahmed Rasheed,Weishi Yuan,Ivan Kos,Ines Batinic-Haberle,Siân Jones,Gregory J. Riggins,Henry S. Friedman,Allan H. Friedman,David A. Reardon,James E. Herndon,Kenneth W. Kinzler,Victor E. Velculescu,Bert Vogelstein,Darell D. Bigner +17 more
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Lenny Dang,David W. White,Stefan Gross,Bryson D. Bennett,Mark A. Bittinger,Edward M. Driggers,Valeria Fantin,Hyun Gyung Jang,Shengfang Jin,Marie C. Keenan,Kevin Marks,Robert M. Prins,Patrick S. Ward,Katharine E. Yen,Linda M. Liau,Joshua D. Rabinowitz,Lewis C. Cantley,Craig B. Thompson,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Shinsan M. Su +20 more
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
D. Williams Parsons,Siân Jones,Xiaosong Zhang,Jimmy Lin,Rebecca J. Leary,Philipp Angenendt,Parminder Mankoo,Hannah Carter,I-Mei Siu,Gary L. Gallia,Alessandro Olivi,Roger E. McLendon,B.K. Ahmed Rasheed,Stephen T. Keir,Tatiana Nikolskaya,Yuri Nikolsky,Dana A. Busam,Hanna Tekleab,Luis A. Diaz,James Hartigan,Doug R. Smith,Robert L. Strausberg,Suely Kazue Nagahashi Marie,Sueli Mieko Oba Shinjo,Hai Yan,Gregory J. Riggins,Darell D. Bigner,Rachel Karchin,Nick Papadopoulos,Giovanni Parmigiani,Bert Vogelstein,Victor E. Velculescu,Kenneth W. Kinzler +32 more