Recurrent Gene Deletion Is a Potential Clinical Marker in Early-Onset Colorectal Cancer and Is Involved in the Regulation of Cell Migration.

The incidence of early-onset colorectal cancer (EOCRC; age younger than 50 years) has been progressively increasing over the last decades globally, with causes unexplained. A distinct molecular feature of EOCRC is that compared with cases of late-onset colorectal cancer, in EOCRC cases, there is a higher incidence of ( somatic deletions. However, the mechanisms of in early-onset colorectal carcinogenesis are currently unknown. In this study, we show that in 30% of EOCRCs with heterozygous deletion of , there were pathogenic mutations in this gene, suggesting that can be inactivated by deletion or mutation in EOCRC. To study the role of in EOCRC, CRISPR/cas9 technology was employed to generate knockout HCT-116 (EOCRC) and HS-5 (bone marrow) cell lines. loss in these cell lines did not perturb Nodal pathway signaling nor cell proliferation. Expression microarrays, RNA sequencing, and protein expression analysis by LC-IMS/MS showed that inactivation deregulates other signaling pathways independent of the Nodal pathway, such as epithelial-mesenchymal transition and cell migration. Significantly, loss increased the migration capacity of CRC cells. Additionally, a gut-specific conditional KO mouse model revealed no subsequent tumor development in mice. Overall, these findings suggest that could play a secondary role in early-onset colorectal carcinogenesis because its loss increases the migration capacity of CRC cells. Therefore, further study is warranted to explore other signalling pathways deregulated by loss that may play a significant role in the pathogenesis of the disease.