A Gene Expression and Pre-mRNA Splicing Signature That Marks the Adenoma-Adenocarcinoma Progression in Colorectal Cancer

It is widely accepted that most colorectal cancers (CRCs) arise from colorectal adenomas (CRAs), but transcriptomic data characterizing the progression from colorectal normal mucosa to adenoma, and then to adenocarcinoma are scarce. These transition steps were investigated using microarrays, both at the level of gene expression and alternative pre-mRNA splicing. Many genes and exons were abnormally expressed in CRAs, even more than in CRCs, as compared to normal mucosae. Known biological pathways involved in CRC were altered in CRA, but several new enriched pathways were also recognized, such as the complement and coagulation cascades. We also identified four intersectional transcriptional signatures that could distinguish CRAs from normal mucosae or CRCs, including a signature of 40 genes differentially deregulated in both CRA and CRC samples. A majority of these genes had been described in different cancers, including FBLN1 or INHBA, but only a few in CRC. Several of these changes were also observed at the protein level. In addition, 20% of these genes (i.e. CFH, CRYAB, DPT, FBLN1, ITIH5, NR3C2, SLIT3 and TIMP1) showed altered pre-mRNA splicing in CRAs. As a global variation occurring since the CRA stage, and maintained in CRC, the expression and splicing changes of this 40-gene set may mark the risk of cancer occurrence from analysis of CRA biopsies.