Under the Radar: Survival Strategies of an Ancient Clonally Transmissible Canine Tumor

Canine transmissible venereal tumor (CTVT) is a parasitic cancer clone that has propagated for thousands of years via sexual transfer of malignant cells. Little is understood about the mechanisms that converted an ancient tumor into the world’s oldest known continuously propagating somatic cell lineage. We created the largest existing catalog of canine genome-wide variation and compared it against two CTVT genome sequences, thereby separating alleles derived from the founder’s genome from somatic drivers of clonal transmissibility. We show that CTVT is exquisitely adapted to its transmissible allograft niche, with overlapping mutations at every step of immunosurveillance, particularly MHC Class I antigen presentation and apoptosis. We also identified chronologically early somatic mutations in oncogenesis and immune-related genes that likely represent key initiators of clonal transmissibility. Thus, we provide the first insights into the specific genomic aberrations that underlie CTVT’s dogged perseverance in canids around the world.

犬传染性生殖道肿瘤（Canine transmissible venereal tumor, CTVT）是一种通过恶性细胞的性接触传播而存续数千年的寄生性癌症克隆株。目前学界对其从古老肿瘤演变为全球已知最古老的持续增殖体细胞谱系的机制仍知之甚少。本研究构建了目前已公开的最大规模犬全基因组变异目录，并将其与两株CTVT基因组序列进行比对分析，由此将源自创始细胞基因组的等位基因与介导克隆传播性的体细胞驱动突变区分开来。研究结果表明，CTVT高度适配其传播性同种异体移植微环境，在免疫监视的各个环节均存在重叠突变，尤其集中于主要组织相容性复合体I类（MHC Class I）抗原呈递与细胞凋亡通路。此外，本研究还在肿瘤发生与免疫相关基因中鉴定出时序早期体细胞突变，这类突变或为克隆传播性的关键起始诱因。综上，本研究首次揭示了支撑CTVT在全球犬科动物群体中顽强存续的特异性基因组畸变。