Somatic evolution and global expansion of an ancient transmissible cancer lineage

The canine transmissible venereal tumour (CTVT) is a cancer lineage that arose several millennia ago and survives by ‘metastasising’ between hosts via 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 but subsequently vanished, correlate ultraviolet-light mutagenesis with tumour latitude, and describe tumours 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 drift is the dominant feature of long-term cancer evolution

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

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.Wellcome Trust Investigator Award, 102942/Z/13/A Elizabeth P Murchison Leverhulme Trust Philip Leverhulme Prize Elizabeth P Murchison Royal Society Research Grant, RG130615 Elizabeth P Murchiso

Somatic evolution and global expansion of an ancient transmissible cancer lineage

Made available in DSpace on 2019-10-06T15:53:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-08-02GPD Charitable TrustLeverhulme TrustThe 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.Transmissible Cancer Group Department of Veterinary Medicine University of CambridgeAnimal Management in Rural and Remote Indigenous Communities (AMRRIC)World VetsAnimal Shelter Stichting Dierenbescherming SurinameSikkim Anti-Rabies and Animal Health Programme Department of Animal Husbandry Livestock Fisheries and Veterinary Services Government of SikkimRoyal (Dick) School of Veterinary Studies Roslin Institute University of Edinburgh Easter Bush CampusConserLab Animal Preventive Medicine Department Faculty of Animal and Veterinary Sciences University of ChileCorozal Veterinary Hospital University of PanamáSt. George's UniversityNakuru District Veterinary Scheme LtdAnimal Medical CentreInternational Animal Welfare Training Institute UC Davis School of Veterinary MedicineCentro Universitário de Rio Preto (UNIRP)Department of Clinical and Veterinary Surgery São Paulo State University (UNESP)Ladybrand Animal ClinicVeterinary Clinic Sr. Dog'sWorld Vets Latin America Veterinary Training CenterNational Veterinary Research InstituteAnimal ClinicIntermunicipal Stray Animals Care Centre (DIKEPAZ)Animal Protection Society of SamoaFaculty of Veterinary Science University of ZuliaVeterinary Clinic BIOCONTROLFaculty of Veterinary Medicine School of Health Sciences University of ThessalyVeterinary Clinic El Roble Animal Healthcare Network Faculty of Animal and Veterinary Sciences University of ChileOnevetGroup Hospital Veterinário BernaUniversidade Vila VelhaVeterinary Clinic ZoovetservisÉcole Inter-états des Sciences et Médecine Vétérinaires de DakarDepartment of Small Animal Medicine Faculty of Veterinary Medicine Utrecht UniversityVetexpert Veterinary GroupVeterinary Clinic Lopez QuintanaClinique Veterinaire de Grand Fond Saint Gilles les BainsDepartment of Veterinary Sciences University of MessinaFacultad de Medicina Veterinaria y Zootecnia Universidad Autónoma del Estado de MéxicoSchool of Veterinary Medicine Universidad de las AméricasCancer Development and Innate Immune Evasion Lab Champalimaud Center for the UnknownTouray and Meyer Vet ClinicHillside Animal HospitalKampala Veterinary SurgeryAsavet Veterinary CharitiesVets Beyond BordersFaculty of Veterinary Medicine Autonomous University of YucatanLaboratorio de Patología Veterinaria Universidad de CaldasInterdisciplinary Centre of Research in Animal Health (CIISA) Faculty of Veterinary Medicine University of LisbonFour Paws InternationalHelp in SufferingVeterinary Clinic Dr José RojasDepartment of Biotechnology Balochistan University of Information Technology Engineering and Management SciencesCorozal Veterinary ClinicVeterinary Clinic VetmasterState Hospital of Veterinary MedicineJomo Kenyatta University of Agriculture and TechnologyLaboratory of Biomedicine and Regenerative Medicine Department of Clinical Sciences Faculty of Animal and Veterinary Sciences University of ChileFaculty of Veterinary and Agricultural Sciences University of MelbourneAnimal Anti Cruelty LeagueClinical Sciences Department Faculty of Veterinary Medicine BucharestDepartment of Pathology Faculty of Veterinary Medicine Ankara UniversityFaculty of Veterinary Sciences National University of AsuncionLilongwe Society for Protection and Care of Animals (LSPCA)Wellcome Sanger InstituteDepartment of Cellular and Molecular Medicine University of California San DiegoDepartment of Clinical and Veterinary Surgery São Paulo State University (UNESP)Leverhulme Trust: 102942/Z/13/

Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer

Abstract: 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

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

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

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. © 2020, The Author(s)