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The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants.
Rio-Machin, Ana; Vulliamy, Tom; Hug, Nele; Walne, Amanda; Tawana, Kiran; Cardoso, Shirleny; Ellison, Alicia; Pontikos, Nikolas; Wang, Jun; Tummala, Hemanth; Al Seraihi, Ahad Fahad H; Alnajar, Jenna; Bewicke-Copley, Findlay; Armes, Hannah; Barnett, Michael; Bloor, Adrian; Bödör, Csaba; Bowen, David; Fenaux, Pierre; Green, Andrew; Hallahan, Andrew; Hjorth-Hansen, Henrik; Hossain, Upal; Killick, Sally; Lawson, Sarah; Layton, Mark; Male, Alison M; Marsh, Judith; Mehta, Priyanka; Mous, Rogier; Nomdedéu, Josep F; Owen, Carolyn; Pavlu, Jiri; Payne, Elspeth M; Protheroe, Rachel E; Preudhomme, Claude; Pujol-Moix, Nuria; Renneville, Aline; Russell, Nigel; Saggar, Anand; Sciuccati, Gabriela; Taussig, David; Toze, Cynthia L; Uyttebroeck, Anne; Vandenberghe, Peter; Schlegelberger, Brigitte; Ripperger, Tim; Steinemann, Doris; Wu, John; Mason, Joanne.
Affiliation
  • Rio-Machin A; Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. a.rio-machin@qmul.ac.uk.
  • Vulliamy T; Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK. t.vulliamy@qmul.ac.uk.
  • Hug N; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • Walne A; Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.
  • Tawana K; Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.
  • Cardoso S; Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.
  • Ellison A; Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.
  • Pontikos N; Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.
  • Wang J; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • Tummala H; Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.
  • Al Seraihi AFH; Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • Alnajar J; Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.
  • Bewicke-Copley F; Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • Armes H; Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • Barnett M; The Leukemia/BMT Program of British Columbia, Division of Hematology, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • Bloor A; Department of Haematology, Christie Hospital, Manchester, UK.
  • Bödör C; MTA-SE Lendulet Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
  • Bowen D; Department of Haematology, St James's University Hospital, Leeds, UK.
  • Fenaux P; Service d'hématologie Séniors, Hôpital St Louis/Université Paris, Paris, France.
  • Green A; National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
  • Hallahan A; Children's Health Queensland Hospital and Health Service, Queensland Children's Hospital, South Brisbane, QLD, Australia.
  • Hjorth-Hansen H; Department of Hematology, St Olavs Hospital and Institute of Cancer Research and Molecular Medicine (IKM) Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
  • Hossain U; Department of Haematology, Whipps Cross Hospital, Barts NHS Trust, London, UK.
  • Killick S; Department of Haematology, The Royal Bournemouth Hospital NHS Foundation Trust, Bournemouth, UK.
  • Lawson S; Department of Haematology, Birmingham Children's Hospital, Birmingham, UK.
  • Layton M; Centre for Haematology, Imperial College London, Hammersmith Hospital, London, UK.
  • Male AM; Clinic Genetics Unit, Great Ormond Street Hospital, London, UK.
  • Marsh J; Department of Haematological Medicine, Haematology Institute, King's College Hospital, London, UK.
  • Mehta P; Bristol Haematology Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
  • Mous R; UMC Utrecht Cancer Center, Universitair Medisch Centrum Utrecht, Huispostnummer, Utrecht, Netherlands.
  • Nomdedéu JF; Laboratori d´Hematologia, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
  • Owen C; Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, AB, Canada.
  • Pavlu J; Centre for Haematology, Imperial College London, Hammersmith Hospital, London, UK.
  • Payne EM; Department of Haematology, UCL Cancer Institute, University College London, London, UK.
  • Protheroe RE; Bristol Haematology Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
  • Preudhomme C; Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France.
  • Pujol-Moix N; Jean-Pierre Aubert Research Center, INSERM, Universitaire de Lille, Lille, France.
  • Renneville A; Laboratori d´Hematologia, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
  • Russell N; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Saggar A; Centre for Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
  • Sciuccati G; Clinical Genetics, St George's Hospital Medical School, London, UK.
  • Taussig D; Servicio de Hematologia y Oncologia, Hospital de Pediatría "Prof. Dr. Juan P. Garrahan", Ciudad Autonoma de Buenos Aires, Argentina.
  • Toze CL; Haemato-oncology Department, Royal Marsden Hospital, Sutton, UK.
  • Uyttebroeck A; The Leukemia/BMT Program of British Columbia, Division of Hematology, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • Vandenberghe P; Department of Hematology, University Hospitals Leuven, Leuven, Belgium.
  • Schlegelberger B; Department of Hematology, University Hospitals Leuven, Leuven, Belgium.
  • Ripperger T; Institut für Humangenetik, Medizinische Hochschule Hannover, Hannover, Germany.
  • Steinemann D; Institut für Humangenetik, Medizinische Hochschule Hannover, Hannover, Germany.
  • Wu J; Institut für Humangenetik, Medizinische Hochschule Hannover, Hannover, Germany.
  • Mason J; British Columbia Children's Hospital, Vancouver, BC, Canada.
Nat Commun ; 11(1): 1044, 2020 02 25.
Article in En | MEDLINE | ID: mdl-32098966
The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Myelodysplastic Syndromes / Leukemia, Myeloid, Acute / Germ-Line Mutation Type of study: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2020 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Myelodysplastic Syndromes / Leukemia, Myeloid, Acute / Germ-Line Mutation Type of study: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2020 Type: Article