Integrative analysis reveals the direct and indirect interactions between DNA copy number aberrations and gene expression changes.
BACKGROUND
DNA copy number aberrations (CNAs) and gene expression (GE) changes provide valuable information for studying chromosomal instability and its consequences in cancer. While it is clear that the structural aberrations and the transcript levels are intertwined, their relationship is more complex and subtle than initially suspected. Most studies so far have focused on how a CNA affects the expression levels of those genes contained within that CNA.


RESULTS
To better understand the impact of CNAs on expression, we investigated the correlation of each CNA to all other genes in the genome. The correlations are computed over multiple patients that have both expression and copy number measurements in brain, bladder and breast cancer data sets. We find that a CNA has a direct impact on the gene amplified or deleted, but it also has a broad, indirect impact elsewhere. To identify a set of CNAs that is coordinately associated with the expression changes of a set of genes, we used a biclustering algorithm on the correlation matrix. For each of the three cancer types examined, the aberrations in several loci are associated with cancer-type specific biological pathways that have been described in the literature: CNAs of chromosome (chr) 7p13 were significantly correlated with epidermal growth factor receptor signaling pathway in glioblastoma multiforme, chr 13q with NF-kappaB cascades in bladder cancer, and chr 11p with Reck pathway in breast cancer. In all three data sets, gene sets related to cell cycle/division such as M phase, DNA replication and cell division were also associated with CNAs. Our results suggest that CNAs are both directly and indirectly correlated with changes in expression and that it is beneficial to examine the indirect effects of CNAs.


BACKGROUND
The code is available upon request.
Lee
Hyunju
H
Harvard-Partners Center for Genetics and Genomics, Informatics Program, Children's Hospital, Department of Cardiology, Children's Hospital, Boston, MA, USA.
Kong
Sek Won
SW
Park
Peter J
PJ
D003198:Computer Simulation; D004252:DNA Mutational Analysis / Q000379:methods*; D004273:DNA, Neoplasm / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D018511:Systems Integration
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins