| First Author | Cuello HA | Year | 2024 |
| Journal | JCI Insight | Volume | 9 |
| Issue | 16 | PubMed ID | 38990656 |
| Mgi Jnum | J:353447 | Mgi Id | MGI:7713726 |
| Doi | 10.1172/jci.insight.181539 | Citation | Cuello HA, et al. (2024) Human-specific elimination of epithelial Siglec-XII suppresses the risk of inflammation-driven colorectal cancers. JCI Insight 9(16) |
| abstractText | Carcinomas are common in humans but rare among closely related "great apes." Plausible explanations, including human-specific genomic alterations affecting the biology of sialic acids, are proposed, but causality remains unproven. Here, an integrated evolutionary genetics-phenome-transcriptome approach studied the role of SIGLEC12 gene (encoding Siglec-XII) in epithelial transformation and cancer. Exogenous expression of the protein in cell lines and genetically engineered mice recapitulated approximately 30% of the human population in whom the protein is expressed in a form that cannot bind ligand because of a fixed, homozygous, human-universal missense mutation. Siglec-XII-null cells/mice recapitulated the remaining approximately 70% of the human population in whom an additional polymorphic frameshift mutation eliminates the entire protein. Siglec-XII expression drove several pro-oncogenic phenotypes in cell lines and increased tumor burden in mice challenged with chemical carcinogen and inflammation. Transcriptomic studies yielded a 29-gene signature of Siglec-XII-positive disease and when used as a computational tool for navigating human data sets, pinpointed with surprising precision that SIGLEC12 expression (model) recapitulates a very specific type of colorectal carcinomas (disease) that is associated with mismatch-repair defects and inflammation, disproportionately affects European Americans, and carries a favorable prognosis. They revealed a hitherto-unknown evolutionary genetic mechanism for an ethnic/environmental predisposition of carcinogenesis. |
