@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 = {<p>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, \&gt;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.</p>
},
	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}
}
