Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences the risk of acute myeloid leukemia
Abstract
Abstract Acute myeloid leukemia (AML) is a complex hematologic malignancy with multiple disease subgroups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here, we perform a meta-analysis of 4 published GWAS plus 2 new GWAS, totaling 4710 AML cases and 12 938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P = 1.35 × 10−8; EFR3B, POMC, DNMT3A, and DNAJC27), which also significantly associates with patient survival (P = 6.09 × 10−3). Our analysis also identifies 3 new genome-wide significant risk loci for disease subgroups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P = 7.0 × 10−10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P = 3.28 × 10−8; PARD3B) and 2p21 (rs79918355; P = 1.60 × 10−9; EPCAM). We also investigated loci previously associated with the risk of clonal hematopoiesis (CH) or CH of indeterminate potential and identified several variants associated with the risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease subgroup specific risk loci.
Article Details
Authors (94)
Diyanath Ranasinghe
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Wei-Yu Lin
Department of Medicinal and Applied Chemistry
Sarah E. Fordham
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Abrar Alharbi
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Nicola J. Sunter
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Claire Elstob
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Mohammed H. Nahari
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Yaobo Xu
Catherine Park
Eric Hungate
4University of Chicago Comprehensive Cancer Center, Chicago, IL
Anne Quante
5Institute of Human Genetics, Technical University of Munich, TUM School of Medicine and Health, Klinikum rechts der Isar, TUM University Hospital, Munich, Germany
Konstantin Strauch
Christian Gieger
Andrew Skol
4University of Chicago Comprehensive Cancer Center, Chicago, IL
Thahira Rahman
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Lara Sucheston-Campbell
9Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, MI
Theresa Hahn
10Department of Cancer Prevention, Roswell Park Cancer Institute, Buffalo, NY
Alyssa I. Clay-Gilmour
11Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC
Gail L. Jones
12Department of Haematology, Freeman Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom
Helen J. Marr
12Department of Haematology, Freeman Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom
Graham H. Jackson
12Department of Haematology, Freeman Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom
Tobias Menne
12Department of Haematology, Freeman Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom
Matthew Collin
Newcastle University, Newcastle Upon Tyne, United Kingdom
Adam Ivey
6Alfred Hospital, Melbourne, VIC, Australia
Robert K. Hills
14Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
Alan K. Burnett
15Paul O’Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, United Kingdom
Nigel H. Russell
Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
Jude Fitzgibbon
Richard A. Larson
Michelle M. Le Beau
4University of Chicago Comprehensive Cancer Center, Chicago, IL
Wendy Stock
Olaf Heidenreich
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Amir Enshaei
Dumni Gunasinghe
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Zoë L. Hawking
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Holly Heslop
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Devi Nandana
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Bingjing Di
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Anna Plokhuta
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Imogen T. Brown
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
David J. Allsup
20Centre for Biomedicine, Hull York Medical School, University of Hull, Hull, United Kingdom
Richard S. Houlston
Andrew Collins
22School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
Paul Milne
23Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Jean Norden
23Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Anne M. Dickinson
23Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Clare Lendrem
23Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Ann K. Daly
23Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Louise Palm
24West Midlands Regional Genetics Laboratory, Birmingham Women’s Hospital, Birmingham, United Kingdom
Kim Piechocki
24West Midlands Regional Genetics Laboratory, Birmingham Women’s Hospital, Birmingham, United Kingdom
Sally Jeffries
24West Midlands Regional Genetics Laboratory, Birmingham Women’s Hospital, Birmingham, United Kingdom
Martin Bornhäuser
Christoph Röllig
22Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany
Heidi Altmann
Leo Ruhnke
27Medizinische Klinik und Poliklinik I, University Hospital Carl Gustav Carus Dresden, Technical University of Dresden, Dresden, Germany
Desiree Kunadt
27Medizinische Klinik und Poliklinik I, University Hospital Carl Gustav Carus Dresden, Technical University of Dresden, Dresden, Germany
Lisa Wagenführ
27Medizinische Klinik und Poliklinik I, University Hospital Carl Gustav Carus Dresden, Technical University of Dresden, Dresden, Germany
Heather J. Cordell
Rebecca Darlay
28Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
Mette K. Andersen
Maria C. Fontana
30Institute of Hematology “L. and A. Seràgnoli,” University of Bologna, Bologna, Italy
Giovanni Martinelli
Giovanni Marconi
31Hematology Unit, Ospedale S. Maria delle Croci, University of Bologna, Ravenna, Italy
Miguel A. Sanz
32Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain and CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
José Cervera
32Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain and CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
Inés Gómez-Seguí
32Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain and CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
Thomas Cluzeau
15Service d’Hématologie, Centre Hospitalier Universitaire de Nice, Nice, France
Chimène Moreilhon
33CHU Pasteur, Service d’Hématologie Biologique, Université Côte d’Azur, Nice, France
Sophie Raynaud
33CHU Pasteur, Service d’Hématologie Biologique, Université Côte d’Azur, Nice, France
Heinz Sill
34Division of Hematology, Medical University of Graz, Graz, Austria
Maria Teresa Voso
Hervé Dombret
Meyling Cheok
37Laboratory of Haematology, CHU Lille, Lille, France
Claude Preudhomme
Unité Mixte de Recherche (UMR) 9020-UMR-S 1277-Canther-Cancer Heterogeneity, Plasticity and Resistance to Therapies, Institut de Recherche contre le Cancer de Lille, University of Lille, CNRS, Inserm, Centre Hospitalier Universitaire Lille, Lille, France
Rosemary E. Gale
38Department of Haematology, University College London Cancer Institute, London, United Kingdom
David Linch
38Department of Haematology, University College London Cancer Institute, London, United Kingdom
Julia Weisinger
391st Department of Internal Medicine, Semmelweis University, Budapest, Hungary
Andras Masszi
40Hematology and Lymphoma Unit, National Institute of Oncology, Budapest, Hungary
Daniel Nowak
Wolf-Karsten Hofmann
Amanda Gilkes
42Department of Haematology, University of Cardiff, Cardiff, United Kingdom
Kimmo Porkka
43Helsinki University Hospital Comprehensive Cancer Center, Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland
Jelena D. Milosevic Feenstra
44Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
Robert Kralovics
44Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
Junke Wang
State Key Laboratory for Flexible Electronics (LoFE)
Manja Meggendorfer
46Munich Leukemia Laboratory, Munich, Germany
Torsten Haferlach
7Munich Leukemia Laboratory, Munich, Germany
Szilvia Krizsán
47MTA-SE Lendulet Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
Csaba Bödör
Brian Parkin
49Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
Sami N. Malek
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan
Friedrich Stölzel
8Department of Internal Medicine II, Hematology and Oncology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Kenan Onel
James M. Allan
1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom