{"doi":"10.1172/jci.insight.181539","title":"Human-specific elimination of epithelial Siglec-XII suppresses the risk of inflammation-driven colorectal cancers","abstract":"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.","journal":"JCI Insight","year":2024,"id":461144,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":2,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9462,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE262088"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":807708,"name":"Saptarshi Sinha","orcid":"0000-0002-4100-5727","position":1,"is_corresponding":false},{"id":814460,"name":"Andrea Verhagen","orcid":"0000-0002-0535-4006","position":2,"is_corresponding":false},{"id":400412,"name":"Nissi Varki","orcid":"0000-0001-9839-1254","position":3,"is_corresponding":false},{"id":313878,"name":"Ajit Varki","orcid":"0000-0002-2206-975X","position":4,"is_corresponding":false},{"id":294967,"name":"Pradipta Ghosh","orcid":"0000-0002-8917-3201","position":5,"is_corresponding":false},{"id":1289677,"name":"Héctor Cuello","orcid":"0000-0002-5304-7545","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:04:12.271488Z","pmid":"38990656","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}