Systems Biology Approach to Identify Gene Network Signatures for Colorectal Cancer

In this work, we integrated prior knowledge from gene signatures and protein interactions with gene set enrichment analysis (GSEA), and gene/protein network modeling together to identify gene network signatures from gene expression microarray data. We demonstrated how to apply this approach into discovering gene network signatures for colorectal cancer (CRC) from microarray datasets. First, we used GSEA to analyze the microarray data through enriching differential genes in different CRC-related gene sets from two publicly available up-to-date gene set databases – Molecular Signatures Database (MSigDB) and Gene Signatures Database (GeneSigDB). Second, we compared the enriched gene sets through enrichment score, false-discovery rate, and nominal p-value. Third, we constructed an integrated protein–protein interaction (PPI) network through connecting these enriched genes by high-quality interactions from a human annotated and predicted protein interaction database, with a confidence score labeled for each interaction. Finally, we mapped differential gene expressions onto the constructed network to build a comprehensive network model containing visualized transcriptome and proteome data. The results show that although MSigDB has more CRC-relevant gene sets than GeneSigDB, the integrated PPI network connecting the enriched genes from both MSigDB and GeneSigDB can provide a more complete view for discovering gene network signatures. We also found several important sub-network signatures for CRC, such as TP53 sub-network, PCNA sub-network, and IL8 sub-network, corresponding to apoptosis, DNA repair, and immune response, respectively.