Human‐specific polymorphic pseudogenization of SIGLEC12 protects against advanced cancer progression.

Bibliographic Collection: 
CARTA-Inspired Publication
Publication Type: Journal Article
Authors: Siddiqui, Shoib S; Vaill, Michael; Do, Raymond; Khan, Naazneen; Verhagen, Andrea L; Zhang, Wu; Lenz, Heinz-Josef; Johnson-Pais, Teresa L; Leach, Robin J; Fraser, Gary; Wang, Charles; Feng, Gen-Sheng; Nissi M Varki; Ajit Varki
Year of Publication: 2021
Journal: FASEB Bioadv
Volume: 3
Issue: 2
Pagination: 69-82
Date Published: 2021 Feb
Publication Language: eng
ISSN: 2573-9832

Compared with our closest living evolutionary cousins, humans appear unusually prone to develop carcinomas (cancers arising from epithelia). The gene, which encodes the Siglec-XII protein expressed on epithelial cells, has several uniquely human features: a fixed homozygous missense mutation inactivating its natural ligand recognition property; a polymorphic frameshift mutation eliminating full-length protein expression in ~60%-70% of worldwide human populations; and, genomic features suggesting a negative selective sweep favoring the pseudogene state. Despite the loss of canonical sialic acid binding, Siglec-XII still recruits Shp2 and accelerates tumor growth in a mouse model. We hypothesized that dysfunctional Siglec-XII facilitates human carcinoma progression, correlating with known tumorigenic signatures of Shp2-dependent cancers. Immunohistochemistry was used to detect Siglec-XII expression on tissue microarrays. PC-3 prostate cancer cells were transfected with Siglec-XII and transcription of genes enriched with Siglec-XII was determined. Genomic status was determined for four different cancer cohorts. Finally, a dot blot analysis of human urinary epithelial cells was established to determine the Siglec-XII expressors versus non-expressors. Forced expression in a null carcinoma cell line enriched transcription of genes associated with cancer progression. While Siglec-XII was detected as expected in ~30%-40% of normal epithelia, ~80% of advanced carcinomas showed strong expression. Notably, >80% of late-stage colorectal cancers had a functional allele, correlating with overall increased mortality. Thus, advanced carcinomas are much more likely to occur in individuals whose genomes have an intact gene, likely because the encoded Siglec-XII protein recruits Shp2-related oncogenic pathways. The finding has prognostic, diagnostic, and therapeutic implications.

DOI: 10.1096/fba.2020-00092
Alternate Journal: FASEB Bioadv