IDH1 and IDH2 mutations in gliomas.
BACKGROUND
A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas).


METHODS
We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes.


RESULTS
We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein.


CONCLUSIONS
Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.
Yan
Hai
H
Department of Pathology, Pediatric Brain Tumor Foundation Institute, Duke University Medical Center, Durham, NC 27710, USA. yan00002@mc.duke.edu
Parsons
D Williams
DW
Jin
Genglin
G
McLendon
Roger
R
Rasheed
B Ahmed
BA
Yuan
Weishi
W
Kos
Ivan
I
Batinic-Haberle
Ines
I
Jones
Siân
S
Riggins
Gregory J
GJ
Friedman
Henry
H
Friedman
Allan
A
Reardon
David
D
Herndon
James
J
Kinzler
Kenneth W
KW
Velculescu
Victor E
VE
Vogelstein
Bert
B
Bigner
Darell D
DD
D000328:Adult; D001254:Astrocytoma / Q000235:genetics; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005909:Glioblastoma / Q000235:genetics; D005910:Glioma / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D009837:Oligodendroglioma / Q000235:genetics; D014407:Tumor Cells, Cultured; D055815:Young Adult
C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase