IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas.
TLDR
A total of 130 IDH1 mutations were detected in 321 gliomas of various histological types and biological behaviors, and all were located at amino acid residue 132.Abstract:
IDH1 encodes isocitrate dehydrogenase 1, which participates in the citric acid cycle and was recently reported to be mutated in 12% of glioblastomas. We assessed IDH1 mutations in 321 gliomas of various histological types and biological behaviors. A total of 130 IDH1 mutations was detected, and all were located at amino acid residue 132. Of these, 91% were G→A mutations (Arg→His). IDH1 mutations were frequent in low-grade diffuse astrocytomas (88%) and in secondary glioblastomas that developed through progression from low-grade diffuse or anaplastic astrocytoma (82%). Similarly, high frequencies of IDH1 mutations were found in oligodendrogliomas (79%) and oligoastrocytomas (94%). Analyses of multiple biopsies from the same patient (51 cases) showed that there were no cases in which an IDH1 mutation occurred after the acquisition of either a TP53 mutation or loss of 1p/19q, suggesting that IDH1 mutations are very early events in gliomagenesis and may affect a common glial precursor cell population. IDH1 mutations were co-present with TP53 mutations in 63% of low-grade diffuse astrocytomas and with loss of heterozygosity 1p/19q in 64% of oligodendrogliomas; they were rare in pilocytic astrocytomas (10%) and primary glioblastomas (5%) and absent in ependymomas. The frequent presence of IDH1 mutations in secondary glioblastomas and their near-complete absence in primary glioblastomas reinforce the concept that despite their histological similarities, these subtypes are genetically and clinically distinct entities.read more
Citations
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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.
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.
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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.
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Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases
Wei Xu,Hui Yang,Ying Liu,Ying Yang,Ping Wang,Se Hee Kim,Shinsuke Ito,Chen Yang,Pu Wang,Meng Tao Xiao,Li Xia Liu,Wen Qing Jiang,Jing Liu,Jin Ye Zhang,Bin Wang,Stephen V. Frye,Yi Zhang,Yanhui Xu,Qun-Ying Lei,Kun-Liang Guan,Shimin Zhao,Yue Xiong +21 more
TL;DR: 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases, leading to genome-wide histone and DNA methylation alterations.
Journal ArticleDOI
Mutational Analysis Reveals the Origin and Therapy-Driven Evolution of Recurrent Glioma
Brett E. Johnson,Tali Mazor,Chibo Hong,Michael R. Barnes,Koki Aihara,Cory Y. McLean,Shaun D. Fouse,Shogo Yamamoto,Hiroki R. Ueda,Kenji Tatsuno,Saurabh Asthana,Llewellyn E. Jalbert,Sarah J. Nelson,Andrew W. Bollen,W. Clay Gustafson,Elise Charron,William A. Weiss,Ivan Smirnov,Jun S. Song,Adam B. Olshen,Soonmee Cha,Yongjun Zhao,Richard A. Moore,Andrew J. Mungall,Steven J.M. Jones,Martin Hirst,Marco A. Marra,Nobuhito Saito,Hiroyuki Aburatani,Akitake Mukasa,Mitchel S. Berger,Susan M. Chang,Barry S. Taylor,Joseph F. Costello +33 more
TL;DR: Exome sequencing of exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution.
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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.
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TL;DR: Data is summarized on incidence rates, survival, and genetic alterations from population-based studies of astrocytic and oligodendrogliomas that were carried out in the Canton of Zurich, Switzerland to suggest that the acquisition of TP53 mutations in these glioblastoma subtypes may occur through different mechanisms.
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