Compared to chimpanzees, our closest evolutionary cousins, humans are particularly prone to developing advanced carcinomas — the type of tumors that include prostate, breast, lung and colorectal cancers — even in the absence of known risk factors, such as genetic predisposition or tobacco use.
A recent study led by
researchers at University of California San Diego School of Medicine and Moores
Cancer Center helps explain why. The study, published December 9, 2020 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
percent 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.
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 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 percent 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 percent 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 got a jump start by developing a simple 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.
Journal article: https://faseb.onlinelibrary.wiley.com/doi/10.1096/fba.2020-00092
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