Dogs are hosts to the oldest and most widely disseminated cancer

January 24, 2014 by Artem Kaznatcheev

A little while ago, I got a new friend and roommate: Sugar. She is very docile, loves walks and belly-rubs, but isn’t a huge fan of other dogs. Her previous owner was an elderly woman that couldn’t take Sugar outside during most of the year — if you haven’t heard, Montreal is pretty difficult to walk around during winter. This resulted in less exposure to other dogs leading to an anti-social attitude, and less exercise which (combined with Sugar’s adorable demands for food) made Sugar overweight. She now gets plenty of exercise and is slowly returning to a healthy weight and attitude.

But, you can never be too careful, so Sugar will go in for a check-up on Monday. Just like humans, dogs have many treatable conditions, and for some — like cancer — it is better to catch them early. But when it comes to cancer, there is one things that sets dogs apart from nearly all other species: they are susceptible to one of only two known naturally occurring clonally transmissible cancers — canine transmissible venereal tumor (CTVT).

That’s right, a contagious cancer. More precisely a single clonal line that has been living as as a parasitic life form for over 11,000 years (Murchison, Wedge et al., 2014)!



CTVT was first reported in the medical literature by Blaine (1810) in London as “an ulcerous state, accompanied with a fungous excrescence” (severe cases can be quiet graphic). In 1876, M.A. Novinsky demonstrated that the tumor could be transmitted to a healthy dog by infecting it with tumor cells (Richardson, 1981). This is fundamentally different from all other cancer except the Tasmanian devil facial tumor disease, a contagion of which is threatening their extinction (Miller, et al., 2011). Although we know how to raise or extend the life of tumors in Petri dishes, or that some transmissible viruses (most famous probably being HPV in humans) can cause (or greatly increase the risk of) cancer (Parkin, 2006); the rule is always that any given cancer lives at most as long as its host. But in biology, there are as many exceptions as rules and for this rule an exception is CTVT.

In the case of infection-associated cancers, the pathogen itself is not cancerous, but instead induces the host’s healthy cells to become cancerous. In CTVT, however, the pathogen is the cancer, or put in other words: the cells in the tumor of each dog that’s ever had CTVT are direct descendants of the cells in the first tumor of the first dog to have CTVT. In particular, this means that today the genome of a dog’s CTVT tumor is different from the dog’s own genome and in its cells contains the evolutionary history of the disease since its first case, not just since its appearance in the current host. Murchison, Wedge, et al. (2014) used this fact to study and date the disease.

To learn the age of this cell colony, they used the number of mutations in the tumor’s genome as a molecular clock. They assumed that the clock ticked at the same rate as the mutation signature characterized by C>T at CpG dinucleoties (known as Signature B by the authors, and Signature 1B in Alexandrov et al (2013) where it was established to correlate highly with patient age in human cancers) in human medulloblastoma — 43.3 mutations of this signature per year. This resulted in an age of around 11 thousand years. By looking at the complete tumor genomes of two different dogs in very different parts of the world (Brazil and Australia), Murchison, Wedge et al (2014) were also able to date the widespread dissemination of the cancer (it is now present on all continents except Antarctica) to around 500 years ago during the Age of Discovery.

To give a feeling for numbers, 11 thousand years ago is around when agriculture originated, and wolves were domesticated by European hunter-gatherers around 18 thousand years ago based on dating from mitochondrial DNA (Thalmann et al., 2013).

Today, the tumor cells are effectively a unicellular asexual reproducing but sexual transmitted pathogen. But since much of the now-useless canine DNA is still in the cancer, we can not only date the colony, but also reconstruct the phenotype of the founder animal. It seems that the breed was of limited genetic diversity, which allowed the cancer to escape the hosts’ immune response. Patient zero was of medium to large size with a banded white-black (agouti) or solid black coat, and had pointed ears and snout. Although the original breed is now extinct, the authors conclude that the Alaskan malamutes and huskies are phenotypically closest to the original host. In other words, the first patient looked a lot like Sugar.

This work is exciting to me not only because of the connection to my dog Sugar, but also because it brings back memories of Paul Davies’ view of cancer as “cells reverting to their ancestral single-cell state”. This was an approach that I was skeptical of, as are others, but oddities like this make me want to reconsider. Also, since I think most people would consider an asexual single-cell parasite to be a simpler organism than Sugar, I wonder if CTVT is also a good violation of Julian’s ideas on irreversible evolution. The homogeneity of the CTVT tumor that Murchison, Wedge, et al. (2014) report also seems a stark contrast to the high heterogeneity of human cancers (Fidler, 1978) that we always work hard to model. Finally, it makes me a little sad that we as humans probably created the in-breeding conditions for this cancer to arise, and then through the popular sire effect and our wide travels made it the most widely disseminated cancer in the world.

References

Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A., Behjati, S., Biankin, A. V., … & Teague, J. W. (2013). Signatures of mutational processes in human cancer. Nature.

Blaine, D. P. (1810). A Domestic Treatise on the Diseases of Horses and Dogs. T. Boosey, London.

Fidler, I. J. (1978). Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Research: 38(9), 2651-2660.

Miller, W., Hayes, V. M., Ratan, A., Petersen, D. C., Wittekindt, N. E., Miller, J., … & Schuster, S. C. (2011). Genetic diversity and population structure of the endangered marsupial Sarcophilus harrisii (Tasmanian devil). Proceedings of the National Academy of Sciences, 108(30): 12348-12353.

Murchison, E., Wedge, D.C., Alexandrov, L.B., Fu, B., Martincorena, I., Ning, Z., Tubio, J.M.C., Werner, E.I., Allen, J., De Nardi, A.B., Donelan, E.M., Marino, G., Fassati, A., Campbell, P.J., Yang, F., Burt, A., Weiss, R.A., & Stratton, M.R. (2014). Transmissable dog cancer genome reveals the origin and history of an ancient cell lineage Science, 343, 437-440 DOI: 10.1126/science.1247167

Parkin, D.M. (2006). The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer, 118(12): 3030–44.

Richardson, R.C. (1981). Canine transmissible veneral tumor. Comp. Contin. Educ. Pract. Vet. 3:951-956.

Thalmann, O., Shapiro, B., Cui, P., Schuenemann, V. J., Sawyer, S. K., Greenfield, D. L., … & Wayne, R. K. (2013). Complete Mitochondrial Genomes of Ancient Canids Suggest a European Origin of Domestic Dogs. Science, 342(6160): 871-874.