Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer.

Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for 'selfish' traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby 'selfish' positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells.

Evaluation of a 0.75 × 109 /L absolute neutrophil count cut-off for antimicrobial prophylaxis in canine cancer chemotherapy patients.

Absolute neutrophil count (ANC) cut-offs for antimicrobial prophylaxis in veterinary cancer chemotherapy patients are empirical and vary between institutions. Evidence based cut-offs are vital for antimicrobial stewardship, particularly as global antimicrobial resistance rises. The primary objectives of this study were to evaluate the tolerability of a <0.75 × 109 /l ANC cut-off for antimicrobial prophylaxis in dogs after receiving chemotherapy and its impact on antimicrobial prescription. Predicted nadir ANCs (pnANCs) were stratified into six groups (<0.75 × 109 /l [receiving antimicrobial prophylaxis], 0.75-0.99 × 109 /l, 1-1.49 × 109 /l, 1.5-1.99 × 109 /l, 2.0-3.59 × 109 /l and 3.6-12 × 109 /l [reference interval]). The incidences of post-nadir febrile neutropenia (FN) and non-haematological toxicity (NHT) were compared between groups. Five hundred and eighty-six pnANCs were recorded for 181 dogs. There were four episodes of post-nadir FN and 90 episodes of post-nadir NHT. There was no significant difference in incidence of post-nadir FN (P = .063) or post-nadir NHT (P = .084) between pnANC groups. Antimicrobial prophylaxis was prescribed following 8.8% of the chemotherapy administrations; had cut-off values of <1.0 × 109 /l or <1.5 × 109 /l been used it would have been prescribed in 15.3% and 25.8% of cases respectively. An ANC cut-off of <0.75 × 109 /l for antimicrobial prophylaxis appears to be well tolerated and minimizes the prescription of antimicrobials.

Somatic evolution and global expansion of an ancient transmissible cancer lineage.

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.

Mitochondrial genetic diversity, selection and recombination in a canine transmissible cancer.

Canine transmissible venereal tumour (CTVT) is a clonally transmissible cancer that originated approximately 11,000 years ago and affects dogs worldwide. Despite the clonal origin of the CTVT nuclear genome, CTVT mitochondrial genomes (mtDNAs) have been acquired by periodic capture from transient hosts. We sequenced 449 complete mtDNAs from a global population of CTVTs, and show that mtDNA horizontal transfer has occurred at least five times, delineating five tumour clades whose distributions track two millennia of dog global migration. Negative selection has operated to prevent accumulation of deleterious mutations in captured mtDNA, and recombination has caused occasional mtDNA re-assortment. These findings implicate functional mtDNA as a driver of CTVT global metastatic spread, further highlighting the important role of mtDNA in cancer evolution.