This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Okada, Y. Articles by Louis, D. N. Search for Related Content PubMed PubMed Citation Articles by Okada, Y. Articles by Louis, D. N.

Selection Pressures of TP53 Mutation and Microenvironmental Location Influence Epidermal Growth Factor Receptor Gene Amplification in Human Glioblastomas

The Molecular Neuro-Oncology Laboratory and Molecular Pathology Laboratory, Department of Pathology and Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, 149 13^th St., Charlestown, Massachusetts 02129

Epidermal growth factor receptor (EGFR) gene amplification occurs in glioblastomas as so-called double minutes. Because double minutes are extrachromosomal fragments, selection pressures must operate to maintain high EGFR copy number over multiple cell divisions. In analyses of glioblastoma lysates, EGFR amplification has been observed almost exclusively in glioblastomas harboring wild-type TP53 genes, which raises the alternative hypotheses that TP53 mutation either prevents amplification or selects against maintenance of EGFR-amplified cells. To address these possibilities at the cellular level, we studied 14 glioblastomas for TP53 mutation and EGFR gene amplification status, using fluorescence in situ hybridization (FISH) for the latter. Remarkably, four of the six cases with TP53 mutation had isolated EGFR-amplified cells in different regions, demonstrating that EGFR amplification occurs frequently at the cellular level in TP53-mutant glioblastomas. Thus, TP53 mutation does not prevent EGFR amplification but does not facilitate selection of EGFR-amplified cells. Of the eight cases without TP53 mutation, five had widespread EGFR amplification. In four of these five cases, multiple regions of the tumor were available for examination; FISH demonstrated a gradation of EGFR amplification, with highly amplified cells, primarily at the invading edges rather than the relatively solid tumor centers, suggesting that EGFR overexpression, when selected for in vivo, may be related to tumor invasion.

This article has been cited by other articles:

				E. L. Bearer, J. S. Lowengrub, H. B. Frieboes, Y.-L. Chuang, F. Jin, S. M. Wise, M. Ferrari, D. B. Agus, and V. Cristini Multiparameter Computational Modeling of Tumor Invasion Cancer Res., May 15, 2009; 69(10): 4493 - 4501. [Abstract] [Full Text] [PDF]

				A. Li, J. Walling, S. Ahn, Y. Kotliarov, Q. Su, M. Quezado, J. C. Oberholtzer, J. Park, J. C. Zenklusen, and H. A. Fine Unsupervised Analysis of Transcriptomic Profiles Reveals Six Glioma Subtypes Cancer Res., March 1, 2009; 69(5): 2091 - 2099. [Abstract] [Full Text] [PDF]

				Y. Ruano, T. Ribalta, A. R. de Lope, Y. Campos-Martin, C. Fiano, E. Perez-Magan, J.-L. Hernandez-Moneo, M. Mollejo, and B. Melendez Worse Outcome in Primary Glioblastoma Multiforme With Concurrent Epidermal Growth Factor Receptor and p53 Alteration Am J Clin Pathol, February 1, 2009; 131(2): 257 - 263. [Abstract] [Full Text] [PDF]

				T. Martens, Y. Laabs, H. S. Gunther, D. Kemming, Z. Zhu, L. Witte, C. Hagel, M. Westphal, and K. Lamszus Inhibition of Glioblastoma Growth in a Highly Invasive Nude Mouse Model Can Be Achieved by Targeting Epidermal Growth Factor Receptor but not Vascular Endothelial Growth Factor Receptor-2 Clin. Cancer Res., September 1, 2008; 14(17): 5447 - 5458. [Abstract] [Full Text] [PDF]

				D. A. Engler, G. Mohapatra, D. N. Louis, and R. A. Betensky A pseudolikelihood approach for simultaneous analysis of array comparative genomic hybridizations Biostat., July 1, 2006; 7(3): 399 - 421. [Abstract] [Full Text] [PDF]

				G. Mohapatra, R. A. Betensky, E. R. Miller, B. Carey, L. D. Gaumont, D. A. Engler, and D. N. Louis Glioma Test Array for Use with Formalin-Fixed, Paraffin-Embedded Tissue: Array Comparative Genomic Hybridization Correlates with Loss of Heterozygosity and Fluorescence in Situ Hybridization J. Mol. Diagn., May 1, 2006; 8(2): 268 - 276. [Abstract] [Full Text] [PDF]

				M. Aghi, P. Gaviani, J. W. Henson, T. T. Batchelor, D. N. Louis, and F. G. Barker II Magnetic Resonance Imaging Characteristics Predict Epidermal Growth Factor Receptor Amplification Status in Glioblastoma Clin. Cancer Res., December 15, 2005; 11(24): 8600 - 8605. [Abstract] [Full Text] [PDF]

				M. J. Riemenschneider, W. Mueller, R. A. Betensky, G. Mohapatra, and D. N. Louis In Situ Analysis of Integrin and Growth Factor Receptor Signaling Pathways in Human Glioblastomas Suggests Overlapping Relationships with Focal Adhesion Kinase Activation Am. J. Pathol., November 1, 2005; 167(5): 1379 - 1387. [Abstract] [Full Text] [PDF]

				J. K. Wiencke, K. Aldape, A. McMillan, J. Wiemels, M. Moghadassi, R. Miike, K. T. Kelsey, J. Patoka, J. Long, and M. Wrensch Molecular Features of Adult Glioma Associated with Patient Race/Ethnicity, Age, and a Polymorphism in O6-Methylguanine-DNA-Methyltransferase Cancer Epidemiol. Biomarkers Prev., July 1, 2005; 14(7): 1774 - 1783. [Abstract] [Full Text] [PDF]

				A. Misra, M. Pellarin, J. Nigro, I. Smirnov, D. Moore, K. R. Lamborn, D. Pinkel, D. G. Albertson, and B. G. Feuerstein Array Comparative Genomic Hybridization Identifies Genetic Subgroups in Grade 4 Human Astrocytoma Clin. Cancer Res., April 15, 2005; 11(8): 2907 - 2918. [Abstract] [Full Text] [PDF]

				C. Giannini, J. N. Sarkaria, A. Saito, J. H. Uhm, E. Galanis, B. L. Carlson, M. A. Schroeder, and C. D. James Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme Neuro-oncol, April 1, 2005; 7(2): 164 - 176. [Abstract] [PDF]

				T. E. Van Meter, W. C. Broaddus, H. K. Rooprai, G. J. Pilkington, and H. L. Fillmore Induction of membrane-type-1 matrix metalloproteinase by epidermal growth factor-mediated signaling in gliomas Neuro-oncol, July 1, 2004; 6(3): 188 - 199. [Abstract] [PDF]

				N. Shinojima, K. Tada, S. Shiraishi, T. Kamiryo, M. Kochi, H. Nakamura, K. Makino, H. Saya, H. Hirano, J.-i. Kuratsu, et al. Prognostic Value of Epidermal Growth Factor Receptor in Patients with Glioblastoma Multiforme Cancer Res., October 15, 2003; 63(20): 6962 - 6970. [Abstract] [Full Text] [PDF]