@article {324646, title = {Human-specific polymorphic pseudogenization of SIGLEC12 protects against advanced cancer progression.}, journal = {FASEB Bioadv}, volume = {3}, year = {2021}, month = {2021 Feb}, pages = {69-82}, abstract = {

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.

}, issn = {2573-9832}, doi = {10.1096/fba.2020-00092}, author = {Siddiqui, Shoib S and Vaill, Michael and Do, Raymond and Khan, Naazneen and Verhagen, Andrea L and Zhang, Wu and Lenz, Heinz-Josef and Johnson-Pais, Teresa L and Leach, Robin J and Fraser, Gary and Wang, Charles and Feng, Gen-Sheng and Nissi M Varki and Ajit Varki} }