IDH1 mutations at residue p.R132 (IDH1R132) occur frequently in high-grade gliomas but not in other solid tumors†
Fonnet E. Bleeker
Neurosurgical Center Amsterdam, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Laboratory of Molecular Genetics, The OncoGenomics Center, Institute for Cancer Research and Treatment, University of Torino, Medical School, Candiolo, Italy
Search for more papers by this authorSimona Lamba
Laboratory of Molecular Genetics, The OncoGenomics Center, Institute for Cancer Research and Treatment, University of Torino, Medical School, Candiolo, Italy
Search for more papers by this authorSieger Leenstra
Department of Neurosurgery, St. Elisabeth Ziekenhuis, Tilburg, The Netherlands
Department of Neurosurgery, Erasmus Medical Center, Rotterdam, The Netherlands
Search for more papers by this authorTheo Hulsebos
Department of Neurogenetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Search for more papers by this authorW. Peter Vandertop
Neurosurgical Center Amsterdam, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Neurosurgical Center Amsterdam, Location VU University Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorMilo Frattini
Department of Experimental Oncology, Istituto Nazionale Tumori; Milan, Italy
Laboratory of Molecular Diagnostic Institute of Pathology, Locarno, Switzerland
Search for more papers by this authorFrancesca Molinari
Laboratory of Molecular Diagnostic Institute of Pathology, Locarno, Switzerland
Search for more papers by this authorMargaret Knowles
Section of Experimental Oncology, Leeds Institute for Molecular Medicine, Leeds, United Kingdom
Search for more papers by this authorAniello Cerrato
Institute of Endocrinology and Experimental Oncology, National Council of Research, Naples, Italy
Search for more papers by this authorMonica Rodolfo
Department of Experimental Oncology, Istituto Nazionale Tumori; Milan, Italy
Search for more papers by this authorAldo Scarpa
Department of Pathology, Section of Anatomic Pathology, University of Verona, Verona, Italy
Search for more papers by this authorLara Felicioni
Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy
Search for more papers by this authorFiamma Buttitta
Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy
Search for more papers by this authorSara Malatesta
Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy
Search for more papers by this authorAntonio Marchetti
Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy
Search for more papers by this authorCorresponding Author
Alberto Bardelli
Laboratory of Molecular Genetics, The OncoGenomics Center, Institute for Cancer Research and Treatment, University of Torino, Medical School, Candiolo, Italy
FIRC Institute of Molecular Oncology, Milan, Italy
Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Torino; Medical School, Str prov 142Km 3.95; Candiolo (TO), 10060, ItalySearch for more papers by this authorFonnet E. Bleeker
Neurosurgical Center Amsterdam, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Laboratory of Molecular Genetics, The OncoGenomics Center, Institute for Cancer Research and Treatment, University of Torino, Medical School, Candiolo, Italy
Search for more papers by this authorSimona Lamba
Laboratory of Molecular Genetics, The OncoGenomics Center, Institute for Cancer Research and Treatment, University of Torino, Medical School, Candiolo, Italy
Search for more papers by this authorSieger Leenstra
Department of Neurosurgery, St. Elisabeth Ziekenhuis, Tilburg, The Netherlands
Department of Neurosurgery, Erasmus Medical Center, Rotterdam, The Netherlands
Search for more papers by this authorTheo Hulsebos
Department of Neurogenetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Search for more papers by this authorW. Peter Vandertop
Neurosurgical Center Amsterdam, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Neurosurgical Center Amsterdam, Location VU University Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorMilo Frattini
Department of Experimental Oncology, Istituto Nazionale Tumori; Milan, Italy
Laboratory of Molecular Diagnostic Institute of Pathology, Locarno, Switzerland
Search for more papers by this authorFrancesca Molinari
Laboratory of Molecular Diagnostic Institute of Pathology, Locarno, Switzerland
Search for more papers by this authorMargaret Knowles
Section of Experimental Oncology, Leeds Institute for Molecular Medicine, Leeds, United Kingdom
Search for more papers by this authorAniello Cerrato
Institute of Endocrinology and Experimental Oncology, National Council of Research, Naples, Italy
Search for more papers by this authorMonica Rodolfo
Department of Experimental Oncology, Istituto Nazionale Tumori; Milan, Italy
Search for more papers by this authorAldo Scarpa
Department of Pathology, Section of Anatomic Pathology, University of Verona, Verona, Italy
Search for more papers by this authorLara Felicioni
Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy
Search for more papers by this authorFiamma Buttitta
Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy
Search for more papers by this authorSara Malatesta
Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy
Search for more papers by this authorAntonio Marchetti
Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy
Search for more papers by this authorCorresponding Author
Alberto Bardelli
Laboratory of Molecular Genetics, The OncoGenomics Center, Institute for Cancer Research and Treatment, University of Torino, Medical School, Candiolo, Italy
FIRC Institute of Molecular Oncology, Milan, Italy
Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Torino; Medical School, Str prov 142Km 3.95; Candiolo (TO), 10060, ItalySearch for more papers by this authorCommunicated by Richard Wooster
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 (IDH1R132) 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 IDH1R132 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 IDH1R132 in GBM. Strikingly, no IDH1 mutations were detected in the other tumor types. These data indicate that cancer mutations affecting IDH1R132 are tissue-specific, and suggest that it plays a unique role in the development of high-grade gliomas. Hum Mutat 30, 7–11, 2009. © 2008 Wiley-Liss, Inc.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| humu_20937_sm_Supptable.pdf13.1 KB | Supp. Table |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- Balakrishnan A, Bleeker FE, Lamba S, Rodolfo M, Daniotti M, Scarpa A, van Tilborg AA, Leenstra S, Zanon C, Bardelli A. 2007. Novel somatic and germline mutations in cancer candidate genes in glioblastoma, melanoma, and pancreatic carcinoma. Cancer Res 67: 3545–3550.
- Bleeker FE, Felicioni L, Buttitta F, Lamba S, Cardone L, Rodolfo M, Scarpa A, Leenstra S, Frattini M, Barbareschi M, Grammastro MD, Sciarrotta MG, Zanon C, Marchetti A, Bardelli A. 2008a. AKT1(E17K) in human solid tumours. Oncogene May 26 [Epub ahead of print].
- Bleeker FE, Lamba S, Rodolfo M, Scarpa A, Leenstra S, Vandertop WP, Bardelli A. 2008b. Mutational profiling of cancer candidate genes in glioblastoma, melanoma and pancreatic carcinoma reveals a snapshot of their genomic landscapes. Hum Mutat, in press.
- Chen TR, Dorotinsky CS, McGuire LJ, Macy ML, Hay RJ. 1995. DLD-1 and HCT-15 cell lines derived separately from colorectal carcinomas have totally different chromosome changes but the same genetic origin. Cancer Genet Cytogenet 81: 103–108.
- Geisbrecht BV, Gould SJ. 1999. The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase. J Biol Chem 274: 30527–30533.
- Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. 2008. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321: 1801–1806.
- Koshland Jr DE, Walsh K, LaPorte DC. 1985. Sensitivity of metabolic fluxes to covalent control. Curr Top Cell Regul 27: 13–22.
- Lee SM, Koh HJ, Park DC, Song BJ, Huh TL, Park JW. 2002. Cytosolic NADP(+)-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic Biol Med 32: 1185–1196.
- Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. 2007. WHO classification of tumours of the central nervous system. Lyon: IARC Press.
- Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schuler D, Probst-Hensch NM, Maiorka PC et al. 2004. Genetic pathways to glioblastoma: a population-based study. Cancer Res 64: 6892–6899.
- Ohgaki H, Kleihues P. 2007. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170: 1445–1453.
- Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz Jr LA, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. 2008. An integrated genomic analysis of human glioblastoma multiforme. Science 321: 1807–1812.
- Scherer H. 1940. Cerebral astrocytomas and their derivatives. Am J Cancer 40: 159–198.
- Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. 2006. The consensus coding sequences of human breast and colorectal cancers. Science 314: 268–274.
- Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B. 2007. The genomic landscapes of human breast and colorectal cancers. Science 318: 1108–1113.
- Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, Ding J. 2004. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem 279: 33946–33957.
