Abstract B002: Transmissible cancer in bivalves: Mutation and selection in cancer lineages and host genomes through hundreds of years of evolution

Abstract Transmissible cancers are clonal infectious cancer cell lineages that have evolved into infectious parasitic cell lines that repeatedly engraft from animal to animal through the environment. They occur in dogs, Tasmanian devils and in many species of bivalves (10 species reported so far). The bivalve transmissible neoplasia (BTN) in soft-shell clams was recently identified as transmissible, but the cancer has been observed on the east coast of North America for several decades, causing massive die-offs in populations in New England and Canada in the 1980s and 2000s of up to 90%, but it is currently maintained in those populations at a prevalence of only ∼1-5%. We have assembled a chromosome-scale reference genome for soft-shell clams and have sequenced pure samples of BTN, confirming the clonal nature of these cancers and identifying a deep split between the cancers separated geographically, with distinct sublineages in New England and Prince Edward Island. Using the high-confidence somatic SNVs that occurred since this divergence, we generated a molecular clock that estimates that this cancer lineage is approximately 400 years old. We also observed high levels of genome rearrangement and transposable element activity, as well as a unique mutational signature, likely due to the over-activity of an error-prone polymerase. By following naturally engrafted clams in the lab, we have observed that about half of clams progress to high levels of cancer followed by death, while the other half are long-term non-progressors or are cases in which cancer first grows but then regresses. We are currently conducting analyses to identify loci associated with engraftment by BTN and with severe disease, in order to identify the genetic mechanism of the blocks to cancer progression that appear to have evolved in these population of clams. In contrast to this enzootic maintenance of the disease on the east coast, we have recently discovered an outbreak of this same lineage of BTN in soft-shell clams in Puget Sound, Washington. We have recorded prevalences of >80% in two sites, and local aquaculture and communities are reporting massive die-offs. By comparing the transcriptomic response of the more resistant east coast clams and the more susceptible west coast clams, we will determine what genes are differentially expressed in clams that are able to block cancer growth. Overall, we are using the evolutionary history of these unique models of dramatically long-lived cancer cells to identify genetic mechanisms for blocking cancer. Citation Format: Michael J. Metzger. Transmissible cancer in bivalves: Mutation and selection in cancer lineages and host genomes through hundreds of years of evolution [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B002.