A survey of glioblastoma genomic amplifications and deletions
- 529 Downloads
Glioblastoma Multiforme (GBM) is a malignant brain cancer that develops after accumulating genomic DNA damage that often includes gene amplifications and/or deletions. These copy number changes can be a critical step in brain tumor development. To evaluate glioblastoma genomic copy number changes, we determined the genome-wide copy number alterations in 31 GBMs. Illumina Bead Arrays were used to assay 22 GBMs and Digital Karyotyping was used on 8 GBM cell lines and one primary sample. The common amplifications we observed for all 31 samples was GLI/CDK4 (22.6%), MDM2 (12.9%) and PIK3C2B/MDM4 (12.9%). In the 22 GBM tumors, EGFR was amplified in 22.7% of surgical biopsies. The most common homozygously deleted region contained CDKN2A/CDKN2B (p15 and p16) occurring in 29% of cases. This data was compiled and compared to published array CGH studies of 456 cases of GBMs. Pooling our Illumina data with published studies yielded these average amplification rates: EGFR—35.7%, GLI/CDK4—13.4%, MDM2—9.2%, PIK3C2B/MDM4—7.7%, and PDGFRA—7.7%. The CDKN2A/CDKN2B locus was deleted in 46.4% of the combined cases. This study provides a larger assessment of amplifications and deletions in glioblastoma patient populations and shows that several different copy number technologies can produce similar results. The main pathways known to be involved in GBM tumor formation such as p53 control, growth signaling, and cell cycle control are all represented by amplifications or deletions of critical pathway genes. This information is potentially important for formulating targeted therapy in glioblastoma and for planning genomic studies.
KeywordsGlioblastoma multiforme Oncogenomics Genomic amplifications Homozygous deletions SNP array Digital karyotyping Copy number alterations Whole genome scans
This research was supported by NIH Grant NS052507 and the Virginia and D. K. Ludwig Fund for Cancer Research. G. J. R. is the Irving J. Sherman M.D. Professor of Neurosurgery Research.
- 1.Pinkel D, Segraves R, Sudar D, Clark S, Poole I, Kowbel D, Collins C, Kuo WL, Chen C, Zhai Y, Dairkee SH, Ljung BM, Gray JW, Albertson DG (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 20(2):207–211CrossRefPubMedGoogle Scholar
- 4.Gunderson KL, Kruglyak S, Graige MS, Garcia F, Kermani BG, Zhao C, Che D, Dickinson T, Wickham E, Bierle J, Doucet D, Milewski M, Yang R, Siegmund C, Haas J, Zhou L, Oliphant A, Fan JB, Barnard S, Chee MS (2004) Decoding randomly ordered DNA arrays. Genome Res 14(5):870–877CrossRefPubMedGoogle Scholar
- 6.Kleihues P, Burger PC, Plate KH, Ohgaki H, Cavenee WK (2000) Pathology and genetics: tumors of the nervous system. International Agency for Research on Cancer, LyonGoogle Scholar
- 11.Ruano Y, Mollejo M, Ribalta T, Fiano C, Camacho FI, Gomez E, de Lope AR, Hernandez-Moneo JL, Martinez P, Melendez B (2006) Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling. Mol Cancer 5:39CrossRefPubMedGoogle Scholar
- 12.Maher EA, Brennan C, Wen PY, Durso L, Ligon KL, Richardson A, Khatry D, Feng B, Sinha R, Louis DN, Quackenbush J, Black PM, Chin L, DePinho RA (2006) Marked genomic differences characterize primary and secondary glioblastoma subtypes and identify two distinct molecular and clinical secondary glioblastoma entities. Cancer Res 66(23):11502–11513CrossRefPubMedGoogle Scholar
- 13.Kotliarov Y, Steed ME, Christopher N, Walling J, Su Q, Center A, Heiss J, Rosenblum M, Mikkelsen T, Zenklusen JC, Fine HA (2006) High-resolution global genomic survey of 178 gliomas reveals novel regions of copy number alteration and allelic imbalances. Cancer Res 66(19):9428–9436CrossRefPubMedGoogle Scholar
- 15.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 LA Jr, 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(5897):1807–1812CrossRefPubMedGoogle Scholar
- 17.Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Janne PA (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316(5827):1039–1043CrossRefPubMedGoogle Scholar