Functional network analysis reveals extended gliomagenesis pathway maps and three novel MYC-interacting genes in human gliomas.
Gene expression profiling has proven useful in subclassification and outcome prognostication for human glial brain tumors. The analysis of biological significance of the hundreds or thousands of alterations in gene expression found in genomic profiling remains a major challenge. Moreover, it is increasingly evident that genes do not act as individual units but collaborate in overlapping networks, the deregulation of which is a hallmark of cancer. Thus, we have here applied refined network knowledge to the analysis of key functions and pathways associated with gliomagenesis in a set of 50 human gliomas of various histogenesis, using cDNA microarrays, inferential and descriptive statistics, and dynamic mapping of gene expression data into a functional annotation database. Highest-significance networks were assembled around the myc oncogene in gliomagenesis and around the integrin signaling pathway in the glioblastoma subtype, which is paradigmatic for its strong migratory and invasive behavior. Three novel MYC-interacting genes (UBE2C, EMP1, and FBXW7) with cancer-related functions were identified as network constituents differentially expressed in gliomas, as was CD151 as a new component of a network that mediates glioblastoma cell invasion. Complementary, unsupervised relevance network analysis showed a conserved self-organization of modules of interconnected genes with functions in cell cycle regulation in human gliomas. This approach has extended existing knowledge about the organizational pattern of gene expression in human gliomas and identified potential novel targets for future therapeutic development.
Bredel
Markus
M
Division of Oncology, Center for Clinical Sciences Research, Stanford University School of Medicine, Stanford, California 94305-5151, USA. mbredel@stanford.edu
Bredel
Claudia
C
Juric
Dejan
D
Harsh
Griffith R
GR
Vogel
Hannes
H
Recht
Lawrence D
LD
Sikic
Branimir I
BI
D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D016259:Genes, myc / Q000235:genetics*; D005910:Glioma / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011956:Receptors, Cell Surface / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; C097051:epithelial membrane protein-1; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases