Origin, evolution, and global spread of a transmissible cancer clone

Change log
Lawlor, Máire Julia 

Clonally transmissible cancers are malignant cellular clones that spread between unrelated individuals by the physical transfer of living cancer cells. These clones can ‘metastasise’ through populations, having adapted to transmit across external environments and evade the host immune response. Canine Transmissible Venereal Tumour (CTVT) is a sexually transmitted genital tumour that affects dogs and has spread through dog populations worldwide. CTVT is the oldest known transmissible cancer and first arose thousands of years ago from the somatic cells of a single, ‘founder’ dog. The broad aim of this thesis was to advance understanding of biological features underlying CTVT’s continued survival, as well as the evolutionary history that framed the origin of CTVT. In the first part of this thesis, I profile global tumour diversity using complete mitochondrial genome sequences (mtDNA) from 449 CTVT tumours collected from 39 countries in the first large-scale examination of CTVT clonal diversity. Phylogenetic characterisation of this clonal lineage showed that CTVT has captured mtDNA from transient hosts by horizontal transfer at least five times, defining distinct CTVT clades. Phylogeographic patterns and timings suggest the rapid, recent, multi-route dispersal of CTVT, likely via historic sea routes. Negative selection acts on tumour mtDNA to prevent the accumulation of deleterious mutations and there is evidence for multiple, complex mtDNA recombinations in CTVT. This is the first observed instance of mtDNA recombination in cancer. Enrichment of this data set with almost 200 additional mtDNAs uncovered further horizontal transfer and recombination events. These findings provide genetic evidence underpinning the importance of functional mitochondria in CTVT evolution. In the second part of this thesis, by analysing genomic data from ancient and modern canids alongside CTVT whole genomes, I describe the ancestry of the CTVT founder and the likely spatiotemporal origin of the disease. The CTVT progenitor belonged to a monophyletic lineage of high-latitude dogs that likely originated in North East Asia and dispersed into the Americas alongside people. Using a pair of CTVT biopsies derived from a naturally occurring direct transmission with a known transmission time interval, I estimated the somatic mutation rate in CTVT and inferred the time of CTVT origin. Finally, I make a case for systematically screening cancers with high prevalence in wildlife species for a transmissible cancer etiology. This work traces the emergence of CTVT, along with detailed geographical and temporal routes of transmissible cancer disease spread over the past two thousand years, and offers new perspectives on the history of dogs as well as key insights into biological mechanisms driving the hitchhiking cancer that has accompanied them around the world.

Murchison, Elizabeth
Cancer, Evolution, Canine Transmissible Venereal Tumour, Transmissible Cancer, CTVT, Canine Genetics, Contagious Cancer, Precontact Dogs, Cancer Biology, Mitochondrial Biology
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge