[ScienceDaily] Evolution may be responsible for the high risk of cancer progression in humans


Most people no longer produce the Siglec-12 protein, but a few still do, meaning their risk of developing cancer doubles.

– Compared with chimpanzees, our closest evolutionary cousins, humans are particularly prone to developing metastatic carcinoma – tumors that include prostate, breast, lung and colorectal cancer – even in the absence of known risk factors such as genetic predisposition or tobacco use.

– A recent study published December 9, 2020 in FASEB BioAdvances, by researchers at the University of California San Diego School of Medicine and Moores Cancer Center helps explain why, the study found found that “an evolutionary genetic mutation unique to humans may be part of the cause.”

“At some point in human evolution, the SIGLEC12 gene — and more specifically the Siglec-12 protein it makes as part of the immune system — was mutated that eliminated the ability to distinguish between ‘self’ and the bacteria get in, so the body needs to get rid of it,” says lead author Ajit Varki, MD, Distinguished Professor at UC San Diego School of Medicine and Moores Cancer Center. “But it hasn’t completely disappeared from the population – it appears that this dysfunctional form of the Siglec-12 protein has become rogue and now becomes a hindrance to bodies that still produce them. ”

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

In a study of normal and cancerous tissue samples, researchers found that about 30 percent of people who still produce the Siglec-12 protein have a lifetime risk of developing terminal cancer. Their levels were more than twice that of those who could not produce Siglec -12.

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Normally, the genes that encode these dysfunctional proteins are eliminated by the body over time and about two-thirds of the global population has stopped producing the Siglec-12 protein. Where the gene persists in humans, it has long been thought to be unrelated to function, and there has been little follow-up research in the two decades since it was discovered. Meanwhile, chimpanzees still produce active Siglec-12.

– When Nissi Varki’s team started detecting Siglec-12 in normal tissue samples using antibodies against the protein, about 30 percent of the samples were positive, as would be expected from the genetic information. In contrast, the majority of advanced cancer samples from the same population were positive for the Siglec-12 protein.

Following a group of patients with end-stage colorectal cancer, the researchers found that more than 80 percent had a functional form of the SIGLEC-12 gene, and these patients had worse outcomes than a group of patients with advanced colorectal cancer. a small number of patients with other end-stage colorectal cancer.

“These results suggest that a small number of people who are still able to make proteins have a much higher risk of late-stage cancer,” said Nissi Varki.

The researchers also confirmed their findings in mice by artificially introducing tumor cells to produce Siglec-12. As a result, compared with tumor cells without active Siglec-12, the cancer grew faster and opened up many known biological pathways involved in metastatic cancers.

According to Ajit Varki, this information is important because it can be used for future diagnosis and treatment. The team got off to a great start by developing a simple urine test that can be used to detect the presence of a dysfunctional protein, and “we can also use antibodies.” able to fight Siglec-12 to deliver selective chemotherapy to tumor cells carrying protein dysfunction, without harming normal cells,” he said.

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– Other study co-authors include: Shoib S. Siddiqui, Michael Vaill, Raymond Do, Naazneen Khan, Andrea L. Verhagen, Gen-Sheng Feng, UC San Diego; Wu Zhang, Heinz-Josef Lenz, University of Southern California; Teresa L. Johnson-Pais, Robin J. Leach, University of Texas Health Science Center; and Gary Fraser, Charles Wang, Loma Linda University.

-Funding for this study came in part from the National Institutes of Health (grant R01GM32373, 5U01CA086402, T32GM008666 and DK007202).

– More: Professor Ajit Varki is a scientific advisor for Mlytics Inc., a biotech startup developing this new Siglec-targeted immunotherapy in solid tumours. Mlytics has also funded a related research collaboration with UC San Diego led by Nissi Varki.

The source:

Materials provided by the University of California – San Diego. Original written by Heather Buschman. Note: Content may have been modified in presentation and length.


Shoib S Siddiqui et al. Human-specific polymorphic pseudogenization of SIGLEC12 protects against advanced cancer progression. FASEB BioAdvances, 08 December 2020. DOI: 10.1096/fba.2020-00092

Editor: Roxie Duong

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