Open AccessNetwork modeling of the transcriptional effects of copy number aberrations in glioblastoma
Author(s) -
Jörnsten Rebecka,
Abenius Tobias,
Kling Teresia,
Schmidt Linnéa,
Johansson Erik,
Nordling Torbjörn E M,
Nordlander Bodil,
Sander Chris,
Gennemark Peter,
Funa Keiko,
Nilsson Björn,
Lindahl Linda,
Nelander Sven
Publication year - 2011
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.1038/msb.2011.17
Subject(s) - biology , glioblastoma , computational biology , genetics , cancer research
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.