Research Article

Somatic evolution and global expansion of an ancient transmissible cancer lineage

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Science  02 Aug 2019:
Vol. 365, Issue 6452, eaau9923
DOI: 10.1126/science.aau9923

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It's a dog's life

Canine transmissible venereal tumor is one of the few cancer lineages that is transferred among individuals through contact. It arose millennia ago and has been evolving independently from its hosts ever since. Baez-Ortega et al. looked at the phylogenetic history of the cancer and describe several distinctive mutational patterns (see the Perspective by Maley and Shibata). Most notably, both positive and negative selection show only weak or distant signals. This suggests that the main driver of the lineage's evolution is neutral genetic drift. Understanding the influence of drift may reshape how we think about long-term cancer evolution.

Science, this issue p. eaau9923; see also p. 440

Structured Abstract


The canine transmissible venereal tumor (CTVT) is a sexually transmitted cancer that manifests as genital tumors in dogs. This cancer first arose in an individual “founder dog” several thousand years ago and has since survived by transfer of living cancer cells to new hosts during coitus. Today, CTVT affects dogs around the world and is the oldest and most prolific known cancer lineage. CTVT thus provides an opportunity to explore the evolution of cancer over the long term and to track the unusual biological transition from multicellular organism to obligate conspecific asexual parasite. Furthermore, the CTVT genome, acting as a living biomarker, has recorded the changing mutagenic environments experienced by this cancer throughout millennia and across continents.


To capture the genetic diversity of the CTVT lineage, we analyzed somatic mutations extracted from the protein-coding genomes (exomes) of 546 globally distributed CTVT tumors. We inferred a time-resolved phylogenetic tree for the clone and used this to trace the worldwide spread of the disease and to select subsets of mutations acquired at known geographical locations and time periods. Computational methods were applied to extract mutational signatures and to measure their exposures across time and space. In addition, we assessed the activity of selection using ratios of nonsynonymous and synonymous variants.


The CTVT phylogeny reveals that the lineage first arose from its founder dog 4000 to 8500 years ago, likely in Asia, with the most recent common ancestor of modern globally distributed tumors occurring ~1900 years ago. CTVT underwent a rapid global expansion within the past 500 years, likely aided by intensification of human maritime travel. We identify a highly specific mutational signature dominated by C>T mutations at GTCCA pentanucleotide contexts, which operated in CTVT up until ~1000 years ago. The number of mutations caused by ultraviolet light exposure is correlated with latitude of tumor collection, and we identify CTVTs with heritable hyperactivity of an endogenous mutational process. Several “driver” mutation candidates are identified in the basal trunk of the CTVT tree, but there is little evidence for ongoing positive selection. Although negative selection is detectable, its effect is largely confined to genes with known essential functions, thus implying that CTVT predominantly evolves through neutral processes.


We have traced the evolution of a transmissible cancer over several thousand years, tracking its spread across continents and contrasting the mutational processes and selective forces that molded its genome with those described in human cancers. The identification of a highly context-specific mutational process that operated in the past but subsequently vanished, as well as correlation of ultraviolet light–induced DNA damage with latitude, highlight the potential for long-lived, widespread clonal organisms to act as biomarkers for mutagenic exposures. Our results suggest that neutral genetic drift is the dominant evolutionary force operating on cancer over the long term, in contrast to the ongoing positive selection that is often observed in short-lived human cancers. The weakness of negative selection in this asexual lineage may be expected to lead to the progressive accumulation of deleterious mutations, invoking Muller’s ratchet and raising the possibility that CTVT may be declining in fitness despite its global success.

Cancer evolution over thousands of years.

The canine transmissible venereal tumor (CTVT) is an ancient contagious cancer with a global distribution. We sequenced the exomes of 546 CTVT tumors and identified somatic single-nucleotide variants (SNVs). These were used to construct a time-resolved phylogenetic tree, yielding insights into the cancer’s phylogeography, mutational processes, and signatures of selection across thousands of years. Notably, a highly context-specific mutational pattern named signature A was identified, which was active in the past but ceased to operate about 1000 years ago. BP, years before present.


The canine transmissible venereal tumor (CTVT) is a cancer lineage that arose several millennia ago and survives by “metastasizing” between hosts through cell transfer. The somatic mutations in this cancer record its phylogeography and evolutionary history. We constructed a time-resolved phylogeny from 546 CTVT exomes and describe the lineage’s worldwide expansion. Examining variation in mutational exposure, we identify a highly context-specific mutational process that operated early in the cancer’s evolution but subsequently vanished, correlate ultraviolet-light mutagenesis with tumor latitude, and describe tumors with heritable hyperactivity of an endogenous mutational process. CTVT displays little evidence of ongoing positive selection, and negative selection is detectable only in essential genes. We illustrate how long-lived clonal organisms capture changing mutagenic environments, and reveal that neutral genetic drift is the dominant feature of long-term cancer evolution.

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