Why study dogs and cancer?

Innumerable cases of cancer arise each year throughout the animal kingdom. As far as we're aware, that cancer has only twice outlived the animal in which it originated by spreading to new hosts. One of these forms of cancer strikes the Tasmanian Devil and appears to have evolved within the last few hundred years. The second circulates among dogs, and its origin has been harder to pin down.

Now, researchers have sequenced the genomes of two cases that originated in Australia and Brazil and have shown that the cancer contains a mixture of markers. Some of them are from wolves and some are from domestic dogs, suggesting the cancer originated very close to the origin of dogs as a distinct population. Once established, the cancer circulated among a limited population of dogs for over 10,000 years before going global about 400 years ago.

We've actually known about the cancer since 1810, when the first report of it was published in London. It tends to be a sexually transmitted disease, causing large growths in the mouth or genital tract before the immune system gets it under control. Once controlled, the growths vanish and the dog remains immune for the rest of its life.

The authors of the new study obtained two samples of the tumor from two very different (and distant) sources: an Aboriginal camp dog in Australia and an American Cocker Spaniel from the east coast of Brazil. A look at the chromosomes of the tumors showed that although they may have originated in a dog, that happened long ago in their past. Instead of the 39 sets of chromosomes that dogs have, the tumor had about 50, the majority of which were complicated mixtures of pieces from normal dog chromosomes. Through these rearrangements, 640 genes have been lost entirely.

Many segments were present multiple times, while a few were only no longer paired. One of those unpaired copies was the sex chromosome. The tumor has only a single X, making it impossible to know whether it was from a female (but lost one of its two Xs), or male (but lost its copy of the Y).

Enlarge / The normal dog genome (left) vs. the two different cancer genomes. The number of chromosomes and the order of genes on them have been completely scrambled in the cancer.

Image courtesy of Elizabeth Murchison

To get a finer-grained picture, the authors sequenced the genomes of the two tumors, along with those of their hosts. The chaos at the chromosome level is repeated in the individual bases of the DNA. The authors estimate that the tumors have about 1.9 million mutations that change individual bases; the typical human tumor will have between 1,000 and 5,000. In fact, the two different tumors each had 100,000 mutations that were distinct to them.

Many of these mutations had significant consequences. Nearly half of the 23,000 genes in the dog genome had also picked up a mutation in the tumor. But comparison between the Australian and Brazil samples suggested that very few of the new mutations were adaptive; this suggests that most of the changes that allowed the tumor to thrive outside its original host took place early in its evolution.

With the two genomes and a large collection of dog and wolf genetic data available, the authors were able to say something about the tumor's origin. Based on partial genetic data, earlier estimates had placed the origin at anywhere from 400 to 70,000 years ago. The new work narrows that range down considerably, placing it between 10,000 and 13,000 years ago, with a most likely date of 11,300 years.

That's right about the time that dogs were thought to have been domesticated. In keeping with that, the tumor has a mix of the genetic variants known to be associated with dog domestication; some of those variants look like they originated with dogs, and others look like they came from wolves (the researchers could also tell that the cancer's original host was large and had a black or agouti coat). Placing it on the canine family tree suggested it was most closely related to huskies and Alaskan malamutes, breeds thought to be relatively ancient (although their age has been questioned).

In contrast to the age of the tumor, the two different cancer samples appear to have shared a common ancestor fairly recently—only about 400 years ago—despite being very distant geographically. That timing corresponds to the start of the era of European exploration and colonization and suggests that the tumor had been lurking in Europe until human travelers inadvertently allowed it to go global by taking their dogs with them.

The other thing that's clear from the genetics is that the tumor's original host didn't have a lot of genetic diversity, which implies that it came from a small, inbred population. The other case of a transmissible cancer, the one from Tasmania, also strikes a population with limited genetic diversity. The authors suggest that this may be the key to giving the cancer its original ability to spread. With the entire population looking genetically similar, the cancer cells wouldn't look as obviously foreign to its new host, allowing them to evade immune attack. And with 11,000 years of evolution, the cancer has had plenty of opportunity to refine its evasion techniques.