Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells

TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2?/? mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2?/? tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2?/? Lin?c-Kit+ cells shows higher mutation frequencies in Tet2?/? cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis

Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells

TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2-/- mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2-/- tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2-/- Lin-c-Kit+ cells shows higher mutation frequencies in Tet2-/- cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis

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.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

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas

Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates the development of germinal center (GC)-derived lymphomas in mice. In both human and murine lymphomas, CREBBP loss-of-function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses, including class II MHC. Mechanistically, CREBBP-regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we found to bind extensively to MHC class II loci. HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo Hence, CREBBP loss-of-function contributes to lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, suggesting HDAC3-targeted therapy as a precision approach for CREBBP-mutant lymphomas.SignificanceOur findings establish the tumor suppressor function of CREBBP in GC lymphomas in which CREBBP mutations disable acetylation and result in unopposed deacetylation by BCL6/SMRT/HDAC3 complexes at enhancers of B-cell signaling and immune response genes. Hence, inhibition of HDAC3 can restore the enhancer histone acetylation and may serve as a targeted therapy for CREBBP-mutant lymphomas. Cancer Discov; 7(1); 38-53. ©2016 AACR.See related commentary by Höpken, p. 14This article is highlighted in the In This Issue feature, p. 1