Infectious cancer hasn’t done much over the last 4,000 years

Cancer is a horrific disease, with its damage only limited by the fact that it only harms the individual in which it arises—except when it . In a few extremely rare cases, cancerous cells have evolved the ability to move from host to host, essentially becoming an immortalized parasite. The best known instance of this is in dogs, where a cancer has essentially become a sexually transmitted disease.

While the cancer’s been known about for some time, there’s been a bit of confusion about its origins. Now, a huge team of researchers has looked at parts of the genome gathered from hundreds of dogs from around the globe, and they’ve reconstructed the cancer’s history and evolution. In the process, the team found that it’s not actually doing much evolving anymore.

Dogs can catch cancer while having sex

It’s hard to know what to call this thing. Cancer? Parasite? Disease? To an extent, its formal name covers things nicely: canine transmissible venereal tumor, or CTV. As the “venereal” implies, dogs transmit CTV during sex. It results in tumor growth, often on the external genitalia. But, unlike the cancer spreading among Tasmanian devils, the immune system quickly suppresses CTV, and the tumors quickly regress. But it does last long enough to spread throughout dog populations. With fewer working dogs and strays, CTV is rare in Europe and North America, but it remains prevalent elsewhere.

Figuring out how CTV came about has been challenging, in part because the genetics are a bit confusing. It appears to have arisen in a dog breed that is very old, making it look very old itself. But it’s also picked up mitochondria and their genomes from the dogs it has infected, leading to a completely different picture of its inheritance when that’s considered. To get a detailed picture of what was going on, the research team spent over a decade collecting CTV samples from 43 different countries, ending up with 546 of them in total.

Using those samples, they sequenced the DNA of what’s called the exome, which includes every bit of DNA that is made into a protein. While that’s only about two percent of the total dog genome, it is enough to provide some indication of where the tumor first appeared. In addition, it let the researchers figure out how many mutations the cancer picked up over its history. This provides some perspective on how the cancer has evolved over this period.

In humans, cancers pick up mutations rapidly. That’s in part because they pick up mutations that disable proteins that repair DNA damage, and in part because the cells lose the ability to stop dividing when their DNA is damaged. The same thing seems to have happened with the CTV cells, which have picked up an impressive number of mutations. The research team determined that each million bases of coding DNA has picked up nearly 3,400 individual base changes and another 380 small insertions or losses of bases. That’s a staggering mutational load, higher than any seen in human cancers.

Going global

Based on the different mutations picked up by different lineages, it’s possible to figure out which ones are closest to the base of the evolutionary tree started when CTV evolved. And by tracking mutations that occur with a clock-like frequency, it’s possible to figure out when that happened. These calculations suggest that CTV originated between 4,000 and 8,500 years ago, with a most likely value of 6,2200 years ago. The earliest branches of the evolutionary tree appear to be in India and near the Black Sea, suggesting an origin in central Asia.

CTV appears to have been a local phenomenon until about 2,000 years ago, when these first branches in its lineage occur. But in recent centuries, its spread has accelerated dramatically and gotten a bit chaotic. It showed up in the Americas with the arrival of Europeans about 500 years ago. The American lineages have since spread to Africa at least five times, and those lineages also made it back to Europe and Asia. Meanwhile, another European lineage made it to Australia and started spreading into the Pacific from there. Its spread also took it to the Americas and into Africa at least twice.

A lot of the mutations in CTV seem to have been caused by exposure to UV when the tumor develops on the external genitalia of dogs. This also provides regional information. UV-caused mutations are about seven times higher in samples collected in the tropics than they are in those from closer to the poles.

What’s changed?

With all these mutations in the protein coding regions of genes, it’s worth looking at the damage they do to the proteins those genes encode, as this can tell us something about the changes that keep cancer growing rapidly and help it evade a strong immune response.

While different mutations are present in different lineages, they collectively do some serious damage to CTV’s ability to produce proteins. Nearly a third of the genes have picked up mutations that cause them to produce a protein that is truncated, with translation stopping before the full protein is made. Nearly three quarters of the genes—14,400 in all—have a mutation that alters one of the amino acids in the protein.

If these mutations damaged CTV’s ability to grow and spread to new hosts, they’d end up being selected against by evolution. But, for the most part, that’s not true. When compared to mutations that don’t change a protein’s composition, there was little difference in frequency, suggesting that most mutations are neutral in evolutionary terms. Selection against changes in essential genes were found in only 269 genes, suggesting that there aren’t a lot of proteins that are truly essential to keep a complex cell alive and dividing. (Though many others may be needed to keep it dividing without picking up this sort of damage.)

But there are some mutations that seem to be critical to having made CTV cancerous in the first place. In humans, these are called “driver mutations,” as they help drive a cell to continue dividing, and usually a handful are present in a given cancer. That seems to be true for CTV as well, which has mutations that inactivate genes that slow down growth and other mutations that activate genes that promote growth. (These strike the genes SETD2, CDKN2A, MYC, PTEN, and RB1, which are well known from human cancers.)

Overall, the data suggests that CTV picked up this handful of critical mutations very early in its history. Since then, most of the mutations it has accumulated are neutral, neither promoting nor hindering its growth and spread. And a remarkably small number of genes seem to have to be protected from picking up damaging mutations.

The thing that’s most unusual about these findings is that the important changes found in CTV don’t seem to be much different from those found in human cancer cells, which are notably limited to infecting just a single individual. There are a lot more mutations that are present in CTV than in human cancers, but those seem to be largely the product of it having been around for thousands of years; most of them appear to be neutral from an evolutionary perspective.

It’s not clear from this analysis what changes have happened that let the cells spread from host to host, and at least temporarily evade immune detection. But sequencing the exome would miss any changes in DNA that controls the activity of nearby genes, so there’s a lot of potential information that this study design would have missed. While we may have figured out the details of CTV’s origin, it’s clear that there’s a lot more work needed if we want to understand its unique lifestyle.

, 2019. DOI: 10.1126/science.aau9923  (About DOIs).

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