title: Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma.
abstract: Glioblastoma, the most aggressive 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 radioresistance 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.
authors.affiliation: Department of Neurological Surgery (Brain Tumor Research Center), University of California, School of Medicine, San Francisco, California, USA.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Nigro
authors.forename: Anjan
authors.initials: A
authors.lastname: Misra
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Ivan
authors.initials: I
authors.lastname: Smirnov
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.forename: Chandi
authors.initials: C
authors.lastname: Griffin
authors.forename: Natalie
authors.initials: N
authors.lastname: Ozburn
authors.forename: Mingang
authors.initials: M
authors.lastname: Chen
authors.forename: Edward
authors.initials: E
authors.lastname: Pan
authors.forename: Dimpy
authors.initials: D
authors.lastname: Koul
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
authors.forename: Burt G
authors.initials: BG
authors.lastname: Feuerstein
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
mesh_terms: D054392:Adipokines; D001253:Astrocytes / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured / Q000528:radiation effects; D000071451:Chitinase-3-Like Protein 1; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D004247:DNA / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D037102:Lectins; D009361:Neoplasm Invasiveness; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics; D011836:Radiation Tolerance; D015996:Survival Rate
chemical_list: D054392:Adipokines; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D037102:Lectins; D012313:RNA; D004247:DNA