Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma

Janice M. Nigro, Anjan Misra, Li Zhang, Ivan Smirnov, Howard Colman, Chandi Griffin, Natalie Ozburn, Mingang Chen, Edward Pan, Dimpy Koul, W. K Alfred Yung, Burt G. Feuerstein, Kenneth D. Aldape

Research output: Contribution to journalArticle

253 Scopus citations

Abstract

Glioblastoma, the most agressive primary brain tumor in humans, exhibits a large degree of molecular heterogeneity. Understanding the molecular pathology of a tumor and its linkage to behavior is an important foundation for developing and evaluating approaches to clinical management. Here we integrate array-comparative genomic hybridization and array-based gene expression profiles to identify relationships between DNA copy number aberrations, gene expression alterations, and survival in 34 patients with glioblastoma. Unsupervised clustering on either profile resulted in similar groups of patients, and groups defined by either method were associated with survival. The high concordance between these separate molecular classifications suggested a strong association between alterations on the DNA and RNA levels. We therefore investigated relationships between DNA copy number and gene expression changes. Loss of chromosome 10, a predominant genetic change, was associated not only with changes in the expression of genes located on chromosome 10 but also with genome-wide differences in gene expression. We found that CHI3L1/YKL-40 was significantly associated with both chromosome 10 copy number loss and poorer survival. Immortalized human astrocytes stably transfected with CHI3L1/YKL-40 exhibited changes in gene expression similar to patterns observed in human tumors and conferred radio-resistance and increased invasion in vitro. Taken together, the results indicate that integrating DNA and mRNA-based tumor profiles offers the potential for a clinically relevant classification more robust than either method alone and provides a basis for identifying genes important in glioma pathogenesis.

Original languageEnglish (US)
Pages (from-to)1678-1686
Number of pages9
JournalCancer Research
Volume65
Issue number5
DOIs
Publication statusPublished - Mar 1 2005

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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