Network modeling of the transcriptional effects of copy number aberrations in glioblastoma Journal Article
| Authors: | Jörnsten, R.; Abenius, T.; Kling, T.; Schmidt, L.; Johansson, E.; Nordling, T. E. M.; Nordlander, B.; Sander, C.; Gennemark, P.; Funa, K.; Nilsson, B.; Lindahl, L.; Nelander, S. |
| Article Title: | Network modeling of the transcriptional effects of copy number aberrations in glioblastoma |
| Abstract: | DNA copy number aberrations (CNAs) are a hallmark of cancer genomes. However, little is known about how such changes affect global gene expression. We develop a modeling framework, EPoC (Endogenous Perturbation analysis of Cancer), to (1) detect disease-driving CNAs and their effect on target mRNA expression, and to (2) stratify cancer patients into long- and short-term survivors. Our method constructs causal network models of gene expression by combining genome-wide DNA- and RNA-level data. Prognostic scores are obtained from a singular value decomposition of the networks. By applying EPoC to glioblastoma data from The Cancer Genome Atlas consortium, we demonstrate that the resulting network models contain known disease-relevant hub genes, reveal interesting candidate hubs, and uncover predictors of patient survival. Targeted validations in four glioblastoma cell lines support selected predictions, and implicate the p53-interacting protein Necdin in suppressing glioblastoma cell growth. We conclude that large-scale network modeling of the effects of CNAs on gene expression may provide insights into the biology of human cancer. Free software in MATLAB and R is provided. © 2011 EMBO and Macmillan Publishers Limited All rights reserved. |
| Keywords: | cancer survival; controlled study; unclassified drug; oncoprotein; human cell; major clinical study; sunitinib; drug targeting; cancer patient; antineoplastic agent; imatinib; gene expression; cell growth; genetic association; genotype; cancer survivor; cancer genetics; oncogene; messenger rna; glioblastoma; tumor cell line; gefitinib; gene regulatory network; conceptual framework; simvastatin; protein hub; genomic dna; quantitative trait locus; necdin; cancer genomics; copy number variation; cancer biology; genomic rna; 1 tert butyl 3 [6 (3,5 dimethoxyphenyl) 2 (4 diethylaminobutylamino)pyrido[2,3 d]pyrimidin 7 yl]urea; 5 (4 chlorophenyl) 1 (4 methoxyphenyl) 3 trifluoromethyl 1h pyrazole; enuracil; formycin; jtt 130; ki 23057; ly 333013; mepyramine; sdx 102; voglibose; dna copy number aberration |
| Journal Title: | Molecular Systems Biology |
| Volume: | 7 |
| ISSN: | 1744-4292 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2011-01-01 |
| Language: | English |
| DOI: | 10.1038/msb.2011.17 |
| PROVIDER: | scopus |
| PMCID: | PMC3101951 |
| PUBMED: | 21525872 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 23 June 2011" - "Article No.: 486" - "Source: Scopus" |
