A genome-wide screen reveals functional gene clusters in the cancer genome and identifies EphA2 as a mitogen in glioblastoma

Fenghua Liu, Peter J. Park, Weil Lai, Elizabeth Maher, Arnab Chakravarti, Laura Durso, Xiuli Jiang, Yi Yu, Amanda Brosius, Meredith Thomas, Lynda Chin, Cameron Brennan, Ronald A. DePinho, Isaac Kohane, Rona S. Carroll, Peter M. Black, Mark D. Johnson

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

A novel genome-wide screen that combines patient outcome analysis with array comparative genomic hybridization and mRNA expression profiling was developed to identify genes with copy number alterations, aberrant mRNA expression, and relevance to survival in glioblastoma. The method led to the discovery of physical gene clusters within the cancer genome with boundaries defined by physical proximity, correlated mRNA expression patterns, and survival relatedness. These boundaries delineate a novel genomic interval called the functional common region (FCR). Many FCRs contained genes of high biological relevance to cancer and were used to pinpoint functionally significant DNA alterations that were too small or infrequent to be reliably identified using standard algorithms. One such FCR contained the EphA2 receptor tyrosine kinase. Validation experiments showed that EphA2 mRNA overexpression correlated inversely with patient survival in a panel of 21 glioblastomas, and ligand-mediated EphA2 receptor activation increased glioblastoma proliferation and tumor growth via a mitogen-activated protein kinase-dependent pathway. This novel genome-wide approach greatly expanded the list of target genes in glioblastoma and represents a powerful new strategy to identify the upstream determinants of tumor phenotype in a range of human cancers.

Original languageEnglish (US)
Pages (from-to)10815-10823
Number of pages9
JournalCancer research
Volume66
Issue number22
DOIs
StatePublished - Nov 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Liu, F., Park, P. J., Lai, W., Maher, E., Chakravarti, A., Durso, L., Jiang, X., Yu, Y., Brosius, A., Thomas, M., Chin, L., Brennan, C., DePinho, R. A., Kohane, I., Carroll, R. S., Black, P. M., & Johnson, M. D. (2006). A genome-wide screen reveals functional gene clusters in the cancer genome and identifies EphA2 as a mitogen in glioblastoma. Cancer research, 66(22), 10815-10823. https://doi.org/10.1158/0008-5472.CAN-06-1408