Compared to chimpanzees, our closest evolutionary cousins, humans are particularly prone to developing advanced carcinomas (cancers arising from epithelia) even in the absence of known risk factors, such as genetic predisposition or tobacco use.

Work led by researchers at the University of California (UC), San Diego, School of Medicine and Moores Cancer Center helps explain why. Their study, “Human‐specific polymorphic pseudogenization of SIGLEC12 protects against advanced cancer progression,” published in FASEB BioAdvances, suggests that an evolutionary genetic mutation unique to humans may be at least partly to blame.

“At some point during human evolution, the SIGLEC12 gene—and more specifically, the Siglec-12 protein it produces as part of the immune system—suffered a mutation that eliminated its ability to distinguish between ‘self’ and invading microbes, so the body needed to get rid of it,” said senior author Ajit Varki, MD, distinguished professor at UC San Diego School of Medicine and Moores Cancer Center.

“But it’s not completely gone from the population—it appears that this dysfunctional form of the Siglec-12 protein went rogue and has now become a liability for the minority of people who still produce it.”

Ajit Varki, who is also co-director of both the Glycobiology Research and Training Center and Center for Academic Research and Training in Anthropogeny, led the study with Nissi Varki, MD, professor of pathology at UC San Diego School of Medicine.

In a study of normal and cancerous tissue samples, the researchers discovered that the approximately 30% of people who still produce Siglec-12 proteins are at more than twice the risk of developing an advanced cancer during their lifetimes, compared to people who cannot produce Siglec-12.

“The SIGLEC12 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,” the investigators wrote.

“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 SIGLEC12 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 SIGLEC12 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 SIGLEC12 allele, correlating with overall increased mortality.

“Thus, advanced carcinomas are much more likely to occur in individuals whose genomes have an intact SIGLEC12 gene, likely because the encoded Siglec‐XII protein recruits Shp2‐related oncogenic pathways. The finding has prognostic, diagnostic, and therapeutic implications.”

Normally, genes that encode such dysfunctional proteins are eliminated by the body over time, and approximately two-thirds of the global human population has stopped producing the Siglec-12 protein. Where the gene still hangs around in humans, it was long thought to be of no functional relevance, and there have been very few follow-up studies over the two decades since it was discovered. Meanwhile, chimpanzees still produce functioning Siglec-12.

When Nissi Varki’s team set out to detect the Siglec-12 in non-cancerous tissue samples using an antibody against the protein, approximately 30% of the samples were positive, as expected from the genetic information. In contrast, the majority of advanced cancer samples from the same populations were positive for the Siglec-12 protein.

Looking at a different population of patients with advanced stage colorectal cancer, the researchers found that more than 80% had the functional form of the SIGLEC-12 gene, and those patients had a worse outcome than the minority of patients without it.

“These results suggest that the minority of individuals who can still make the protein are at much greater risk of having an advanced cancer,” Nissi Varki said.

The researchers also validated their findings in mice by introducing tumor cells engineered to produce Siglec-12. The resulting cancers grew much faster, and turned on many biological pathways known to be involved in advanced cancers, compared to control tumor cells without functioning Siglec-12.

According to Ajit Varki, this information is important because it could be leveraged for future diagnostics and treatments. The team already has developed a urine test that could be used to detect the presence of the dysfunctional protein, and “we might also be able to use antibodies against Siglec-12 to selectively deliver chemotherapies to tumor cells that carry the dysfunctional protein, without harming non-cancerous cells,” he said.

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