title: IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors.
abstract: Systematic sequence profiling of the Glioblastoma Multiforme (GBM) genome has recently led to the identification of somatic mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Interestingly, only the evolutionarily conserved residue R132 located in the substrate binding site of IDH1 was found mutated in GBM. At present, the occurrence and the relevance of p.R132 (IDH1(R132)) variants in tumors other than GBMs is largely unknown. We searched for mutations at position R132 of the IDH1 gene in a panel of 672 tumor samples. These included high-grade glioma, gastrointestinal stromal tumors (GIST), melanoma, bladder, breast, colorectal, lung, ovarian, pancreas, prostate, and thyroid carcinoma specimens. In addition, we assessed a panel of 84 cell lines from different tumor lineages. Somatic mutations affecting the IDH1(R132) residue were detected in 20% (23 of 113) high-grade glioma samples. In addition to the previously reported p.R132H and p.R132S alleles, we identified three novel somatic mutations (p.R132C, p.R132G, and p.R132L) affecting residue IDH1(R132) in GBM. Strikingly, no IDH1 mutations were detected in the other tumor types. These data indicate that cancer mutations affecting IDH1(R132) are tissue-specific, and suggest that it plays a unique role in the development of high-grade gliomas.
authors.affiliation: Neurosurgical Center Amsterdam, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Fonnet E
authors.initials: FE
authors.lastname: Bleeker
authors.forename: Simona
authors.initials: S
authors.lastname: Lamba
authors.forename: Sieger
authors.initials: S
authors.lastname: Leenstra
authors.forename: Dirk
authors.initials: D
authors.lastname: Troost
authors.forename: Theo
authors.initials: T
authors.lastname: Hulsebos
authors.forename: W Peter
authors.initials: WP
authors.lastname: Vandertop
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.forename: Francesca
authors.initials: F
authors.lastname: Molinari
authors.forename: Margaret
authors.initials: M
authors.lastname: Knowles
authors.forename: Aniello
authors.initials: A
authors.lastname: Cerrato
authors.forename: Monica
authors.initials: M
authors.lastname: Rodolfo
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: Lara
authors.initials: L
authors.lastname: Felicioni
authors.forename: Fiamma
authors.initials: F
authors.lastname: Buttitta
authors.forename: Sara
authors.initials: S
authors.lastname: Malatesta
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchetti
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics*; D005910:Glioma / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009154:Mutation
chemical_list: D007521:Isocitrate Dehydrogenase