Abstract
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.
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References
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):207–211
Pollack JR, Perou CM, Alizadeh AA, Eisen MB, Pergamenschikov A, Williams CF, Jeffrey SS, Botstein D, Brown PO (1999) Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat Genet 23(1):41–46
Wang TL, Maierhofer C, Speicher MR, Lengauer C, Vogelstein B, Kinzler KW, Velculescu VE (2002) Digital karyotyping. Proc Natl Acad Sci USA 99(25):16156–16161
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):870–877
Mei R, Galipeau PC, Prass C, Berno A, Ghandour G, Patil N, Wolff RK, Chee MS, Reid BJ, Lockhart DJ (2000) Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays. Genome Res 10(8):1126–1137
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, Lyon
Burton EC, Lamborn KR, Feuerstein BG, Prados M, Scott J, Forsyth P, Passe S, Jenkins RB, Aldape KD (2002) Genetic aberrations defined by comparative genomic hybridization distinguish long-term from typical survivors of glioblastoma. Cancer Res 62(21):6205–6210
Korshunov A, Sycheva R, Golanov A (2006) Genetically distinct and clinically relevant subtypes of glioblastoma defined by array-based comparative genomic hybridization (array-CGH). Acta Neuropathol (Berl) 111(5):465–474
Misra A, Pellarin M, Nigro J, Smirnov I, Moore D, Lamborn KR, Pinkel D, Albertson DG, Feuerstein BG (2005) Array comparative genomic hybridization identifies genetic subgroups in grade 4 human astrocytoma. Clin Cancer Res 11(8):2907–2918
Roerig P, Nessling M, Radlwimmer B, Joos S, Wrobel G, Schwaenen C, Reifenberger G, Lichter P (2005) Molecular classification of human gliomas using matrix-based comparative genomic hybridization. Int J Cancer 117(1):95–103
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 5:39
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):11502–11513
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):9428–9436
Saha S, Sparks AB, Rago C, Akmaev V, Wang CJ, Vogelstein B, Kinzler KW, Velculescu VE (2002) Using the transcriptome to annotate the genome. Nat Biotechnol 20(5):508–512
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):1807–1812
Gallia GL, Rand V, Siu IM, Eberhart CG, James CD, Marie SK, Oba-Shinjo SM, Carlotti CG, Caballero OL, Simpson AJ, Brock MV, Massion PP, Carson BS, Sr, Riggins GJ (2006) PIK3CA gene mutations in pediatric and adult glioblastoma multiforme. Mol Cancer Res 4(10):709–714
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):1039–1043
Huang PH, Cavenee WK, Furnari FB, White FM (2007) Uncovering therapeutic targets for glioblastoma: a systems biology approach. Cell Cycle 6(22):2750–2754
Acknowledgments
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.
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Rao, S.K., Edwards, J., Joshi, A.D. et al. A survey of glioblastoma genomic amplifications and deletions. J Neurooncol 96, 169–179 (2010). https://doi.org/10.1007/s11060-009-9959-4
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DOI: https://doi.org/10.1007/s11060-009-9959-4