Polymorphic Pseudogenization of SIGLEC12 in Humans: Relationship to Late Stage Cancer Progression

Human Siglec‐XII (a receptor encoded by the SIGLEC12 gene) is expressed in tissue macrophages and some epithelial cell surfaces. Humans (but not the closely related “great apes”) harbor a universally fixed missense mutation that eliminated the sialic acid binding property of this protein, a canonical functional feature of all other human Siglecs. Population analysis of the SIGLEC12 locus identified a polymorphic frameshift mutation, which leads to truncation of the Siglec‐XII polypeptide, and loss of expression. The homozygous null state of this mutation is present in all human populations with an average frequency of ~40%, and the locus was independently identified as undergoing an unexplained “negative selective sweep”, apparently favoring the null state. In the current study, immunohistochemistry using a monoclonal antibody to Siglec‐XII showed that while some epithelia in ~35% of normal human tissue samples from human autopsies express Siglec‐XII on epithelial cells (approximately the expected rate based on the frequency of the null state), high expression was observed in about 80% of samples from advanced carcinomas. Genomic studies on population cohorts with a low frequency of carcinomas (Seventh‐day Adventists) and in early stage prostate cancers diagnosed clinically by PSA expression did not show any correlation of disease risk or early‐stage progression with the SIGLEC12 frameshift mutation. In contrast, analysis of two advanced colorectal cancer cohorts (TRIBE and FIRE3) demonstrated that more than 80% of the patients had wild‐type SIGLEC12 . Moreover, in one of the colorectal cancer cohorts (FIRE3), the presence of wild‐type SIGLEC12 was correlated with significantly decreased survival. Meanwhile, gene expression data comparing a tumor cell line transfected with a human SIGLEC12 cDNA with sham‐transfected cells shows upregulation of pathways associated with cancer progression. Taken together, all of these evolutionary clues and experimental findings suggest that while SIGLEC12 likely lost its function in the immune system of humans prior to the origin of our species, its persistence in some humans could be associated with the pathobiology of late stage carcinomas. In this regard, we have taken advantage of the expression of wild type Siglec‐XII on urinary epithelial cells, to develop a simple urine test to check for the expression status of SIGLEC12 . This approach can be combined with future genomic analyses and signaling studies, to explore this unusual human specific evolution of an apparent evolutionary liability. Support or Funding Information The G. Harold & Leila Y. Mathers Charitable Foundation grant This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .