Selection pressures of TP53 mutation and microenvironmental location influence epidermal growth factor receptor gene amplification in human glioblastomas

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,...

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Published in:	Cancer research (Chicago, Ill.) Vol. 63; no. 2; pp. 413 - 416
Main Authors:	OKADA, Yoshifumi, HURWITZ, Edward E, ESPOSITO, John M, BROWER, Melissa A, NUTT, Catherine L, LOUIS, David N
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-01-2003
Subjects:	Biological and medical sciences Gene Amplification Gene Dosage Genes, p53 - genetics glioblastoma Glioblastoma - genetics Humans In Situ Hybridization, Fluorescence Medical sciences Mutation Neurology Paraffin Embedding Receptor, Epidermal Growth Factor - genetics TP53 gene Tumors of the nervous system. Phacomatoses Human Nervous system diseases Tumoral tissue Glioblastoma Cell microenvironment Gene overexpression Malignant tumor Gene expression Epidermal growth factor receptor Site specificity Malignant glioma Gene amplification Growth factor receptor Epidermal growth factor TP53 Gene Central nervous system disease Selection pressure Mutation Tumor suppressor gene
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0008-5472 1538-7445