Pathway-Based Evaluation in Early Onset Colorectal Cancer Suggests Focal Adhesion and Immunosuppression along with Epithelial-Mesenchymal Transition

Colorectal cancer (CRC) has one of the highest incidences among all cancers. The majority of CRCs are sporadic cancers that occur in individuals without family histories of CRC or inherited mutations. Unfortunately, whole-genome expression studies of sporadic CRCs are limited. A recent study used microarray techniques to identify a predictor gene set indicative of susceptibility to early-onset CRC. However, the molecular mechanisms of the predictor gene set were not fully investigated in the previous study. To understand the functional roles of the predictor gene set, in the present study we applied a subpathway-based statistical model to the microarray data from the previous study and identified mechanisms that are reasonably associated with the predictor gene set. Interestingly, significant subpathways belonging to 2 KEGG pathways (focal adhesion; natural killer cell-mediated cytotoxicity) were found to be involved in the early-onset CRC patients. We also showed that the 2 pathways were functionally involved in the predictor gene set using a text-mining technique. Entry of a single member of the predictor gene set triggered a focal adhesion pathway, which confers anti-apoptosis in the early-onset CRC patients. Furthermore, intensive inspection of the predictor gene set in terms of the 2 pathways suggested that some entries of the predictor gene set were implicated in immunosuppression along with epithelial-mesenchymal transition (EMT) in the early-onset CRC patients. In addition, we compared our subpathway-based statistical model with a gene set-based statistical model, MIT Gene Set Enrichment Analysis (GSEA). Our method showed better performance than GSEA in the sense that our method was more consistent with a well-known cancer-related pathway set. Thus, the biological suggestion generated by our subpathway-based approach seems quite reasonable and warrants a further experimental study on early-onset CRC in terms of dedifferentiation or differentiation, which is underscored in EMT and immunosuppression.