An integrated genomic analysis of human glioblastoma multiforme

D Williams Parsons, Siân Jones, Xiaosong Zhang, Jimmy Cheng-Ho Lin, Rebecca J Leary, Philipp Angenendt, Parminder Mankoo, Hannah Carter, I-Mei Siu, Gary L Gallia, Alessandro Olivi, Roger McLendon, B Ahmed Rasheed, Stephen Keir, Tatiana Nikolskaya, Yuri Nikolsky, Dana A Busam, Hanna Tekleab, Luis A Diaz Jr, 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, D Williams Parsons, Siân Jones, Xiaosong Zhang, Jimmy Cheng-Ho Lin, Rebecca J Leary, Philipp Angenendt, Parminder Mankoo, Hannah Carter, I-Mei Siu, Gary L Gallia, Alessandro Olivi, Roger McLendon, B Ahmed Rasheed, Stephen Keir, Tatiana Nikolskaya, Yuri Nikolsky, Dana A Busam, Hanna Tekleab, Luis A Diaz Jr, 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

Abstract

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in 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. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.

Figures

Fig. 1
Fig. 1
Structure of the active site of IDH1. The crystal structure of the human cytosolic NADP(+)–dependent IDH is shown in ribbon format (PDBID: 1T0L) (44). The active cleft of IDH1 consists of a NADP-binding site and the isocitrate-metal ion-binding site. The alpha-carboxylate oxygen and the hydroxyl group of isocitrate chelate the Ca2+ ion. NADP is colored in orange, isocitrate in purple and Ca2+ in blue. The Arg132 residue, displayed in yellow, forms hydrophilic interactions, shown in red, with the alpha-carboxylate of isocitrate. Displayed image was created with UCSF Chimera software version 1.2422 (50).
Fig. 2
Fig. 2
Overall survival according to IDH1 mutation status. The hazard ratio for death among patients with wild-type IDH1 (n = 79), as compared to those with mutant IDH1 (n = 11), was 3.7 (95 percent confidence interval, 2.1 to 6.5; P < 0.001). The median survival was 3.8 years for patients with mutated IDH1, as compared to 1.1 years for patients with wild-type IDH1.

Source: PubMed

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