Centuries of genome instability and evolution in soft-shell clam transmissible cancer

Transmissible cancers are infectious parasitic clones of malignant cells that metastasize to new hosts, living past the death of the founder animal in which the cancer initiated. Several lineages of transmissible cancer have recently been identified in bivalves, including one that has spread through the soft-shell clam (Mya arenaria) population along the east coast of North America. To investigate the evolutionary history of this transmissible cancer lineage, we assembled a highly contiguous 1.2 Gb soft-shell clam reference genome and characterized somatic mutations from cancer sequences. We show that all cancer cases observed descend from a single founder and cluster into two geographically distinct sub-lineages. We discover a previously unreported clock-like mutational signature that predicts the cancer lineage to be 344 to 877 years old, indicating that it spread undetected long before it was first observed in the 1970s. We observe high mutation density, widespread copy number gain, structural rearrangement, loss of heterozygosity, variable telomere lengths, mitochondrial genome expansion, and transposable element activity, all indicative of an unstable cancer genome. Our study reveals the ability for an invertebrate cancer lineage to survive for centuries while its genome continues to structurally mutate, likely contributing to the ability of this lineage to adapt as a parasitic cancer. SUMMARY The genome of a contagious cancer in clams reveals structural instability of multiple types throughout the ∼500 years since its origin.