An Integrated Genomic Analysis of Human Glioblastoma Multiforme

American Association for the Advancement of Science (AAAS) - Tập 321 Số 5897 - Trang 1807-1812 - 2008
D. Williams Parsons1,2,3,4,5, Siân Jones1,2,3,4,5, Xiaosong Zhang1,2,3,4,5, Jimmy Lin1,2,3,4,5, Rebecca J. Leary1,2,3,4,5, Philipp Angenendt1,2,3,4,5, Parminder K. Mankoo1,2,3,4,5, Hannah Carter1,2,3,4,5, I‐Mei Siu1,2,3,4,5, Gary L. Gallia1,2,3,4,5, Alessandro Olivi1,2,3,4,5, Roger E. McLendon1,2,3,4, B. Ahmed Rasheed1,2,3,4, Stephen T. Keir1,2,3,4, Tatiana Nikolskaya1,2,3,4,5, Yuri Nikolsky1,2,3,4,5, Dana Busam1,2,3,4,5, Hanna Tekleab1,2,3,4,5, Luis A. Díaz1,2,3,4,5, James Hartigan1,2,3,4,5, Doug Smith1,2,3,4,5, Robert L. Strausberg1,2,3,4,5, Suely Kazue Nagahashi Marie1,2,3,4,5, Sueli Mieko Oba‐Shinjo1,2,3,4,5, Hai Yan1,2,3,4, Gregory J. Riggins1,2,3,4,5, Darell D. Bigner1,2,3,4, Rachel Karchin1,2,3,4,5, Nikolaos G. Papadopoulos1,2,3,4,5, Giovanni Parmigiani1,2,3,4,5, Bert Vogelstein1,2,3,4,5, Victor E. Velculescu1,2,3,4,5, Kenneth W. Kinzler1,2,3,4,5
1Department of Biomedical Engineering, Institute of Computational Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21218, USA.
2Department of Neurosurgery, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
3Department of Pathology, Pediatric Brain Tumor Foundation, and Preston Robert Tisch Brain Tumor Center at Duke University Medical Center, Durham, NC 27710, USA.
4Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX 77030, USA
5Ludwig Center for Cancer Genetics and Therapeutics, and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.

Tóm tắt

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.

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Contact information for the authors who directed the major components of this project is as follows: H. Yan G. J. Riggins (clinical and sample coordination) [email protected] [email protected]; D. D. Bigner (pathological and clinical review) [email protected]. edu; R. Karchin (bioinformatic analysis) [email protected]; N. Papadopoulos (gene expression analysis) [email protected]; G. Parmigiani (statistical analysis) [email protected]; B. Vogelstein V. E. Velculescu K. W. Kinzler (sequencing and copy number analysis) [email protected] [email protected] [email protected]. We thank N. Silliman J. Ptak L. Dobbyn and M. Whalen for assistance with PCR amplification; D. Lister L. J. Ehinger D. L. Satterfield J. D. Funkhouser and P. Killela for assistance with DNA purification; T. Sjöblom for assistance with database management; the Agencourt sequencing team for assistance with automated sequencing; and C.-S. Liu and the SoftGenetics team for their assistance with mutation detection analyses. This project was carried out under the auspices of the Ludwig Brain Tumor Initiative and was supported by the Virginia and D. K. Ludwig Fund for Cancer Research NIH grants CA121113 NS052507 CA43460 CA57345 CA62924 CA09547 5P50-NS-20023 CA108786 and CA11898 the Pew Charitable Trusts the Pediatric Brain Tumor Foundation Institute the Hirschhorn Foundation Alex's Lemonade Stand Foundation the American Brain Tumor Association the American Society of Clinical Oncology the Brain Tumor Research Fund and Beckman Coulter Corporation. Under separate licensing agreements between the Johns Hopkins University and Genzyme Beckman Coulter and Exact Sciences Corporations B.V. V.E.V. and K.W.K. are entitled to a share of royalties received by the university on sales of products related to research described in this paper. These authors and the university own Genzyme and Exact Sciences stock which is subject to certain restrictions under university policy. The terms of these arrangements are managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.

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American Association for the Advancement of Science (AAAS)

Tập 321 Số 5897

1807-1812

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