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Geneticists Found the 'Master Tumor Suppressor' That Stops Cancer in Elephants

Elephants’ genomes possess 20 copies of a tumor suppressing gene called P53, new research shows.

A longstanding mystery in biology is why the rate of cancer incidence in a species does not scale up with body size and longevity. Take elephants for instance, which live to approximately the same age as humans and have 100 times more cells, yet hardly ever develop cancer, a disease which is estimated to affect 40 percent of Americans at some point in their lives.

You'd expect elephants would have higher rates of cancer, because elephants have significantly more cells than humans and more cells means more opportunities for cancerous mutations to occur. The fact that this isn't the case gives rise to the conundrum known as Peto's Paradox, the resolution of which may provide valuable insight into preventing cancer in humans.

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Recently a team of geneticists led by Joshua Schiffman at the University of Utah made major headway in this direction when they studied the cells of Asian and African elephants from the San Diego Frozen Zoo and found that elephants' genomes possessed 20 copies of a tumor suppressing gene called P53.

"There is definitely a tradeoff, or else many other species would have evolved duplicate P53 genes by now."

For the sake of comparison, the team looked at the genomes of more than 60 other species (including humans) and found that most only possess a single copy of this gene, suggesting that this redundancy in the elephant genome may finally explain the low rate of cancer in the species. The results of the study were published today in an editorial for the Journal of the American Medical Association.

"If you're interested in cancer the first gene to look at is P53, it is the master tumor suppressor," said Vincent Lynch, a human geneticist at the University of Chicago who published supporting research in a preprint study on Biorxiv. "We thought maybe elephants have another copy, but certainly not 19 more copies than other animals. This discovery is a big deal."

According to Lynch, the canonical copy of the P53 gene along with the 19 retrogene copies make elephants more sensitive to DNA damage during cell replication. This hypersensitivity to genetic anomalies means that cells are quicker to 'commit suicide' when they are found to be damaged, halting the proliferation of potentially cancerous cells before it begins.

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While multiple copies of the P53 gene might seem like a wholly positive evolutionary development, the overexpression of this gene likely comes with some tradeoffs, such as reproductive senescence or rapid aging.

"There is definitely a tradeoff, or else many other species would have evolved duplicate P53 genes by now," said Lynch. "We don't know what the tradeoff was, [but] elephants either found a way to deal with it or broke whatever constraint prevented organisms from evolving many P53 copies."

Interestingly, as Lynch and his team noted in their preprint study published on BioRxiv, they were able to trace the redundant development P53 genes back to woolly mammoths and mastodons. Extinct American mastodons, which are smaller than elephants, were only found to have three to eight copies of the gene, whereas woolly and Columbian Mammoths were found to have around 14 copies. According to Lynch, this suggests that the number of copies increased in tandem with body size in the evolution of the elephant lineage.

Ultimately both teams' research only offers a solution to Peto's Paradox rather than the solution. As Lynch was quick to point out, whales are also large and exhibit low incidences of cancer, yet only have one copy P53. Same goes for the naked mole rat, which might be the most uniquely cancer resistant mammal on the planet.

Given that the endgame of all this research is the development of drugs or other clinical tools for the prevention of cancer in humans, the fact that other species have developed different cancer suppression mechanism bodes well for the future. In the meantime though, Lynch said there are plenty of questions to be answered before we see any medical applications coming from these natural suppression mechanisms.

"The big question is how exactly these extra copies are working in the cell, and what other genetic changes in elephants contributes to their augmented cancer resistance?" he said. "It will probably be many decades [before we see clinical applications], but these kinds of discoveries help us better understand basic biological processes, and that is the first step toward translating those discoveries into new treatments."

Correction: An earlier version of this story misidentified Vincent Lynch as the lead author of the study published in JAMA. It was in fact Joshua Schiffman's team at the University of Utah that published the study; Lynch published supporting research in a preprint study on Bioxriv.