Network modeling of the transcriptional effects of copy number aberrations in glioblastoma

Rebecka Jörnsten, Tobias Abenius, Teresia Kling, Linna Schmidt, Erik Johansson, Torbjrn E.M. Nordling, Bodil Nordlander, Chris Sander, Peter Gennemark, Keiko Funa, Björn Nilsson, Linda Lindahl, Sven Nelander

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

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.

Original languageEnglish
Article number486
JournalMolecular Systems Biology
Volume7
DOIs
Publication statusPublished - 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)
  • Applied Mathematics

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