Transcriptional dynamics in colorectal carcinogenesis: new insights into the role of c-Myc and miR17 in benign to cancer transformation.

Colorectal cancer develops in a sequential, evolutionary process, leading to a heterogenic tumor. Comprehensive molecular studies of colorectal cancer have been previously performed; still, the process of carcinogenesis is not fully understood. We utilized gene expression patterns from 94 samples including normal, adenoma, and adenocarcinoma colon biopsies and performed a coexpression network analysis to determine gene expression trajectories of 8,000 genes across carcinogenesis. We found that the majority of gene expression changes occur in the transition from normal tissue to adenoma. The upregulated genes, known to be involved in cellular proliferation, included c-Myc along with its targets. In a cellular model system, we show that physiologic upregulation of c-Myc can lead to cellular proliferation without DNA replication stress. Our analysis also found that carcinogenesis involves a progressive downregulation of genes that are markers of colonic tissue and propose that this reflects a perturbed differentiation of colon cells during carcinogenesis. The analysis of miRNAs targets pointed toward the involvement of miR17 in the regulation of colon cell differentiation. Finally, we found that copy-number variations (CNV) enriched in colon adenocarcinoma tend to occur in genes whose expression changes already in adenoma, with deletions occurring in genes downregulated and duplications in genes upregulated in adenomas. We suggest that the CNVs are selected to reinforce changes in gene expression, rather than initiate them. Together, these findings shed new light into the molecular processes that underlie the transformation of colon tissue from normal to cancer and add a temporal context that has been hitherto lacking.