An Integrated Genomic Analysis of Human Glioblastoma Multiforme

Overview

Journal Science

Specialty Science

Date 2008 Sep 6

PMID 18772396

Citations 2946

Authors

D Williams Parsons

Sian 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

Affiliations

Soon will be listed here.

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.

Citing Articles

Integrating epidemiology and genomics data to estimate the prevalence of acquired cysteine drug targets in the U.S. cancer patient population.

Arun A, Liarakos D, Mendiratta G, Kim J, Goshua G, Olson P Pharmacogenomics J. 2025; 25(1-2):5.

PMID: 40044654 DOI: 10.1038/s41397-025-00364-3.

A Radiologist's Guide to IDH-Wildtype Glioblastoma for Efficient Communication With Clinicians: Part I-Essential Information on Preoperative and Immediate Postoperative Imaging.

Vollmuth P, Karschnia P, Sahm F, Park Y, Ahn S, Jain R Korean J Radiol. 2025; 26(3):246-268.

PMID: 39999966 PMC: 11865903. DOI: 10.3348/kjr.2024.0982.

Research trends in glioma chemoradiotherapy resistance: a bibliometric analysis (2003-2023).

Yu S, Wu J, Jing Y, Lin P, Lang L, Xiong Y Front Oncol. 2025; 15:1539937.

PMID: 39990688 PMC: 11842341. DOI: 10.3389/fonc.2025.1539937.

Modernizing Neuro-Oncology: The Impact of Imaging, Liquid Biopsies, and AI on Diagnosis and Treatment.

Rafanan J, Ghani N, Kazemeini S, Nadeem-Tariq A, Shih R, Vida T Int J Mol Sci. 2025; 26(3).

PMID: 39940686 PMC: 11817476. DOI: 10.3390/ijms26030917.

lioma esource utreach ith upport: A program to identify and initiate supportive care interventions for unmet needs among adult lower-grade glioma patients.

Garcia Fox R, Chukwueke U, Sannes T, Miran D, Chiu D, Bagley C Neurooncol Pract. 2025; 12(1):87-99.

PMID: 39917752 PMC: 11798613. DOI: 10.1093/nop/npae065.

References

Morin R, Bainbridge M, Fejes A, Hirst M, Krzywinski M, Pugh T . Profiling the HeLa S3 transcriptome using randomly primed cDNA and massively parallel short-read sequencing. Biotechniques. 2008; 45(1):81-94. DOI: 10.2144/000112900. View

Louis D, Ohgaki H, Wiestler O, Cavenee W, Burger P, Jouvet A . The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007; 114(2):97-109. PMC: 1929165. DOI: 10.1007/s00401-007-0243-4. View

Velculescu V, Zhang L, Vogelstein B, Kinzler K . Serial analysis of gene expression. Science. 1995; 270(5235):484-7. DOI: 10.1126/science.270.5235.484. View

Gallia G, Rand V, Siu I, Eberhart C, James C, Marie S . PIK3CA gene mutations in pediatric and adult glioblastoma multiforme. Mol Cancer Res. 2006; 4(10):709-14. DOI: 10.1158/1541-7786.MCR-06-0172. View

Thiel G, Marczinek K, Neumann R, WITKOWSKI R, Marchuk D, Nurnberg P . Somatic mutations in the neurofibromatosis 1 gene in gliomas and primitive neuroectodermal tumours. Anticancer Res. 1995; 15(6B):2495-9. View

Hunter C, Smith R, Cahill D, Stephens P, Stevens C, Teague J . A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 2006; 66(8):3987-91. PMC: 7212022. DOI: 10.1158/0008-5472.CAN-06-0127. View

Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E . Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem. 2004; 279(32):33946-57. DOI: 10.1074/jbc.M404298200. View

Jones S, Zhang X, Parsons D, Cheng-Ho Lin J, Leary R, Angenendt P . Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008; 321(5897):1801-6. PMC: 2848990. DOI: 10.1126/science.1164368. View

Stupp R, Mason W, van den Bent M, Weller M, Fisher B, Taphoorn M . Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10):987-96. DOI: 10.1056/NEJMoa043330. View

10.

Maher E, Brennan C, Wen P, Durso L, Ligon K, Richardson A . Marked genomic differences characterize primary and secondary glioblastoma subtypes and identify two distinct molecular and clinical secondary glioblastoma entities. Cancer Res. 2006; 66(23):11502-13. DOI: 10.1158/0008-5472.CAN-06-2072. View

11.

Wong A, Bigner S, Bigner D, Kinzler K, Hamilton S, Vogelstein B . Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci U S A. 1987; 84(19):6899-903. PMC: 299192. DOI: 10.1073/pnas.84.19.6899. View

12.

Kleihues P, Ohgaki H . Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro Oncol. 2001; 1(1):44-51. PMC: 1919466. DOI: 10.1093/neuonc/1.1.44. View

13.

Nekrutenko A, Hillis D, Patton J, Bradley R, Baker R . Cytosolic isocitrate dehydrogenase in humans, mice, and voles and phylogenetic analysis of the enzyme family. Mol Biol Evol. 1998; 15(12):1674-84. DOI: 10.1093/oxfordjournals.molbev.a025894. View

14.

Kil I, Kim S, Lee S, Park J . Small interfering RNA-mediated silencing of mitochondrial NADP+-dependent isocitrate dehydrogenase enhances the sensitivity of HeLa cells toward tumor necrosis factor-alpha and anticancer drugs. Free Radic Biol Med. 2007; 43(8):1197-207. DOI: 10.1016/j.freeradbiomed.2007.07.009. View

15.

Ng P, Henikoff S . SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003; 31(13):3812-4. PMC: 168916. DOI: 10.1093/nar/gkg509. View

16.

Sultan M, Schulz M, Richard H, Magen A, Klingenhoff A, Scherf M . A global view of gene activity and alternative splicing by deep sequencing of the human transcriptome. Science. 2008; 321(5891):956-60. DOI: 10.1126/science.1160342. View

17.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

18.

KRAUS-RUPPERT R, Laissue J, Burki H, ODARTCHENKO N . Proliferation and turnover of glial cells in the forebrain of young adult mice as studied by repeated injections of 3 H-thymidine over a prolonged period of time. J Comp Neurol. 1973; 148(2):211-6. DOI: 10.1002/cne.901480206. View

19.

Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre P . Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004; 64(19):6892-9. DOI: 10.1158/0008-5472.CAN-04-1337. View

20.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S . PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275(5308):1943-7. DOI: 10.1126/science.275.5308.1943. View