ToP: A Trend-of-Disease-Progression Procedure Works Well for Identifying Cancer Genes from Multi-State Cohort Gene Expression Data for Human Colorectal Cancer

Significantly expressed genes extracted from microarray gene expression data have proved very useful for identifying genetic biomarkers of diseases, including cancer. However, deriving a disease related inference from a list of differentially expressed genes has proven less than straightforward. In a systems disease such as cancer, how genes interact with each other should matter just as much as the level of gene expression. Here, in a novel approach, we used the network and disease progression properties of individual genes in state-specific gene-gene interaction networks (GGINs) to select cancer genes for human colorectal cancer (CRC) and obtain a much higher hit rate of known cancer genes when compared with methods not based on network theory. We constructed GGINs by integrating gene expression microarray data from multiple states - healthy control (Nor), adenoma (Ade), inflammatory bowel disease (IBD) and CRC - with protein-protein interaction database and Gene Ontology. We tracked changes in the network degrees and clustering coefficients of individual genes in the GGINs as the disease state changed from one to another. From these we inferred the state sequences Nor-Ade-CRC and Nor-IBD-CRC both exhibited a trend of (disease) progression (ToP) toward CRC, and devised a ToP procedure for selecting cancer genes for CRC. Of the 141 candidates selected using ToP, similar to 50% had literature support as cancer genes, compared to hit rates of 20% to 30% for standard methods using only gene expression data. Among the 16 candidate cancer genes that encoded transcription factors, 13 were known to be tumorigenic and three were novel: CDK1, SNRPF, and ILF2. We identified 13 of the 141 predicted cancer genes as candidate markers for early detection of CRC, 11 and 2 at the Ade and IBD states, respectively.