A Genome-Wide Screen Reveals Functional Gene Clusters in the Cancer Genome and Identifies EphA2 as a Mitogen in Glioblastoma

^{1 1}Department of Neurological Surgery, Brigham and Women's Hospital and Harvard Medical School; ²Program in Neuro-Oncology, Brigham and Women's Hospital and Dana-Farber/Harvard Cancer Center; ³Harvard-Partners Center for Genetics and Genomics; ⁴Center for Applied Cancer Science, Belfer Foundation Institute for Innovative Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute; Departments of ⁵Medicine and Genetics and ⁶Dermatology, Harvard Medical School; and ⁷Children's Hospital Informatics Program, Boston, Massachusetts

^* To whom correspondence should be addressed. E-mail: mjohnson27{at}partners.org.

	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. (Cancer Res 2006; 66(22): 10815-23)

Key Words: microarray, glioblastoma, EphA2, brain tumor, genomics

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