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Evolution, History of Transmissible Dog Cancer Untangled With New Exome Sequences

NEW YORK – An international team has used exome sequencing to dig into origins of the canine transmissible venereal tumor (CTVT) — a form of cancer of the genitals that moves directly from one dog to another during mating via somatic cell clone transfer, amassing somatic mutations along the way.

"[T]he CTVT genome can be considered a living biomarker that records the changing mutagenic environments experienced by this cancer throughout millennia and across continents," the authors noted in their study, published online today in Science.

Along with the clues to the diversity and evolution of the canine cancer itself, the investigators used somatic mutation profiles in hundreds of CTVTs to look at everything from historical exposures to potential, mysterious mutagens in the environment to past mutt and human migrations.

"This tumour has spread to almost every continent, evolving as it spreads," first author Adrian Baez-Ortega, a PhD student in senior author Elizabeth Murchison's comparative oncology and genetics lab in the University of Cambridge Transmissible Cancer Group, said in a statement. "Changes to its DNA tell a story of where it has been and when, almost like a historical travel journal."

Baez-Ortega, Murchison, and their colleagues used exome sequencing to untangle somatic mutation profiles in 546 CTVT samples from pooches collected over more than a decade, from 2003 to 2016, in 43 countries. By comparing the transmissible tumor exomes with 495 normal dog exomes, they narrowed in on more than 148,000 single nucleotide variants, and nearly 12,200 small insertions and deletions.

From there, the team relied on phylogenetic and other analyses to explore CTVT origins and spread. Meanwhile, comparisons with published somatic mutation profiles for half a dozen human cancer types suggested that CTVTs are not subject to the same sorts of host selection displayed by human tumors.

"Our results suggest that neutral genetic drift may be the dominant evolutionary force operating on cancer over the long term, in contrast to the ongoing positive selection that is often observed in human cancers," the authors explained. "Thus, our results suggest that CTVT may have optimized its adaption to the transmissible cancer niche early in its history."

"These canine tumours are foreign bodies, so one would expect to see a battle between them and the dog's immune system, leading to only the strongest tumours successfully being transmitted. This doesn't seem to be happening here," Baez-Ortega added.

Prior research suggests CTVT originated thousands of years ago in a lone 'founder dog,' spreading far and wide since then, the team explained. Although the sexually transmitted cancer has been found in dogs around the world, there is currently little or no CTVT in the West due to free-roaming dog management over the past century.

With the new somatic mutation data, phylogeographic analyses, and founder dog genetics, the team estimated that the transmissible tumor likely originated in Central or Northern Asia some 4,100 to 8,500 years ago, though the CTVTs circulating in present-day dogs today seem to share a common ancestor going back just 1,900 years.

After spreading to the Americas some 500 years ago, a sub-lineage of the transmissible tumor appears to have migrated to Africa several times, while being re-introduced to areas closer to its origins in Asia and Europe, the researchers reported. They suggested that another sub-lineage moved from Asia or Europe to Australia and other parts of the Pacific; to North America; and to Africa.

The researchers identified five mutational signatures in the tumors, including a previously unreported mutational signature that spiked roughly 2,000 years ago, prompting speculation that dogs and humans may have encountered an environmental carcinogen at around that time. 

"It looks like the tumour was exposed to something thousands of years ago that caused changes to its DNA for some length of time and then disappeared," Murchison said in a statement. "It's a mystery what the carcinogen could be. Perhaps it was something present in the environment where the cancer first arose."