Evolution of transmissible cancers
Elizabeth Murchison, Welcome Trust Sanger Inst.
Focussing on two cancers – one in tasmanian devil, the other in dogs.
Every cancer is a somatic outgrowth with it’s own evolutionary process. Cancer is an evolutionary dead end, however, because eventually it leads to the death of the host.
Tasmanian devil facial tumour disease (DFTD) and Canine transmissible venerial tumour (CTVT). In both of these tumours, a clone is transmitted to other individuals, making it able to propagate.
Tasmanian devil: Largest marsupial carnivore, size of a small dog. Habitat is just tasmania.
in 1996, a photographer took a photograph of a tasmanian with a tumour. It was originally thought to be an isolated incident, however, by 2000, there were 2 more cases, by 2002, a lot more tumours were observed. It became clear that they were not isolated cases, but rather a spreading disease. By 2004, had spread through most of tasmania. Only a few pockets now remain disease free. This has been accompanied by a massive decline in tasmanian devil populations. It may in fact lead to the extinction by 2030.
[Some images of the tumours.] Tumours kill the individual within 6 months of first symptoms. It’s likely of schwann cell origin.
Devil has 7 sets of chromosome, while the cancer misses chr2 and is haploid 6. All of the tumours studied all have almost identical karyotypes. That’s highly unusual for cancer. Odd of it happening on it’s own is astronomically small.
Devils tend to bite each other a lot during fighting and mating. This may be the mechanism of transmission. Cancer cells are found in the saliva, so it makes sense.
Predictions based on this proposed mechanism: all the cancers should be genetically identical. The cancers should be genetically different from their hosts.
Microsatelite genotyping. Tumour and normal dna as collected from individuals. Comparing variation, the normals are all variable for microsatelite length, however, the cancer is uniform for length, independent of the length of the microsatelite length.
This, then is unique – one cancer has been spectacularly successful both in propagation, and transmission and longevity.
Next step was to start looking at the DNA of the cancer, then. This was done at Sanger on illumina. De novo assembly was undertaken. Reference genome was also done for tasmanian devil in the process. It was not perfecgt, but was good enough to start studying the cancer.
However, before moving on, they Harvested DNA, flow sorted each chromosome to seaparate, then investigate each chromosome separately. [ok, that’s neat. I haven’t seen that done before.] Helped to improve assembly significantly.
On to the cancer. What’s actually being sequenced is the reference “index case” of the cancer. However, the variation between the cancer and the first individual is less than between individuals, usually. Thus, it can be difficult to separate cancer variations from normals.
Sequenced two tumours, as far apart as possible, to aid in finding somatic SNPs.
First individual “Joey”, about 0.5 SNPs different from reference. Found about 15-18k mutations different from the two cancers. Use this information to build up a phylogeny of the cancers as it spread across the population.
Collected more than 100 tumours and matched normals from across the region. Pick variations from the two cancers selected, and then sample them across the populations sampled. You can use this to identify the heritage patterns of the spread of the cancer.
This can then be used to explain the pattern of the devil tumour movement.
What’s next for the tasmanian devil? Captive breeding programs, island sanctuaries, prevent diseases, vaciine and cures.
Briefly touch on canine cancer. It’s a genital tumour, spread by sexual contact. Found all around the world. Highly transmissible. Evidence confirms that this tumour is all a single clone in dogs.
First identified in 1876 in russia, so it’s at least hundreds of years old, but likely much older than that. May have originally come from wolves, as it’s snps are more similar to wolves than dogs. May be the oldest clone in existance today.
Summary: Only 2 transmissible cancers we know of today. Although they’re similar in mechanism, they’re very different. One has a long lineage, but not so much in the other. Metastasis is common in tasmanian devil, but not in dogs. Tasmanian devil cancer is also not at all sensative to cancer therapies, while dog cancer is.
How about humans? Can human cancers be transmissible? Tested, once, under questionable situations… however, fortunately, it didn’t. However, there is evidence that it can happen, but it requires exceptional circumstances. (example given: Surgeon cut himself while operating on a cancer.)
[Wow, I really enjoyed that talk. Very clear, easy to follow, and interesting subject.]