Transmissible cancers are infectious parasitic clones that metastasize to new hosts, living past the death of the founder animal in which the cancer initiated. We investigated the evolutionary history of a cancer lineage that has spread though the soft-shell clam (Mya arenaria) population by assembling a chromosome-scale soft-shell clam reference genome and characterizing somatic mutations in transmissible cancer. 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. We also discover a previously unreported mutational signature associated with overexpression of an error-prone polymerase and use this to estimate the lineage to be >200 years old. 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 evolution of this lineage as a parasitic cancer.

传染性癌症是一种传染性寄生克隆，它们会转移到新的宿主，在引发癌症的动物死亡后仍然存活。我们通过组装染色体规模的软壳蛤参考基因组并表征传染性癌症中的体细胞突变，研究了在软壳蛤（ Mya  arenararia ）种群中传播的癌症谱系的进化史。我们观察到高突变密度、广泛的拷贝数增加、结构重排、杂合性丧失、端粒长度可变、线粒体基因组扩张和转座元件活性，所有这些都表明癌症基因组不稳定。我们还发现了一个先前未报道的与易错聚合酶过度表达相关的突变特征，并用它来估计该谱系的历史> 200年。我们的研究揭示了无脊椎动物癌症谱系能够存活几个世纪，同时其基因组继续发生结构突变，这可能导致该谱系进化为寄生癌。