Abstract

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.

Details

Title
Genome-wide association study identifies susceptibility loci for acute myeloid leukemia
Author
Wei-Yu, Lin 1   VIAFID ORCID Logo  ; Fordham, Sarah E 1 ; Hungate, Eric 2 ; Sunter, Nicola J 1 ; Elstob Claire 1   VIAFID ORCID Logo  ; Xu Yaobo 1 ; Park, Catherine 1 ; Quante, Anne 3 ; Strauch Konstantin 3 ; Gieger, Christian 4   VIAFID ORCID Logo  ; Skol, Andrew 2 ; Rahman Thahira 1 ; Sucheston-Campbell, Lara 5 ; Wang, Junke 5 ; Hahn, Theresa 6   VIAFID ORCID Logo  ; Clay-Gilmour, Alyssa I 7 ; Jones, Gail L 8 ; Marr, Helen J 8 ; Jackson, Graham H 8 ; Menne, Tobias 8 ; Collin, Mathew 8   VIAFID ORCID Logo  ; Ivey, Adam 9 ; Hills, Robert K 10 ; Burnett, Alan K 11   VIAFID ORCID Logo  ; Russell, Nigel H 12 ; Fitzgibbon, Jude 13   VIAFID ORCID Logo  ; Larson, Richard A 2   VIAFID ORCID Logo  ; Le Beau Michelle M 2 ; Stock, Wendy 2 ; Heidenreich Olaf 1 ; Alharbi Abrar 1 ; Allsup, David J 14   VIAFID ORCID Logo  ; Houlston Richard S 15   VIAFID ORCID Logo  ; Norden, Jean 16 ; Dickinson, Anne M 16 ; Douglas, Elisabeth 16 ; Lendrem Clare 16   VIAFID ORCID Logo  ; Daly, Ann K 16 ; Palm, Louise 17 ; Piechocki, Kim 17 ; Jeffries, Sally 17 ; Bornhäuser, Martin 18 ; Röllig Christoph 19 ; Altmann, Heidi 19 ; Ruhnke, Leo 19 ; Kunadt Desiree 19 ; Wagenführ, Lisa 19 ; Cordell, Heather J 20   VIAFID ORCID Logo  ; Darlay Rebecca 20 ; Andersen, Mette K 21 ; Fontana, Maria C 22 ; Martinelli Giovanni 23 ; Marconi Giovanni 23   VIAFID ORCID Logo  ; Sanz, Miguel A 24   VIAFID ORCID Logo  ; Cervera José 24 ; Gómez-Seguí Inés 24 ; Cluzeau, Thomas 25 ; Chimène, Moreilhon 25 ; Raynaud, Sophie 25 ; Sill Heinz 26   VIAFID ORCID Logo  ; Voso Maria Teresa 27   VIAFID ORCID Logo  ; Lo-Coco, Francesco 27 ; Dombret Hervé 28 ; Cheok Meyling 29   VIAFID ORCID Logo  ; Preudhomme Claude 29 ; Gale, Rosemary E 30 ; Linch, David 30 ; Gaal-Wesinger Julia 31 ; Masszi Andras 32 ; Nowak, Daniel 33   VIAFID ORCID Logo  ; Wolf-Karsten, Hofmann 33 ; Gilkes, Amanda 34 ; Porkka Kimmo 35 ; Milosevic Feenstra Jelena D 36 ; Kralovics, Robert 36 ; Grimwade, David 37 ; Meggendorfer Manja 38 ; Haferlach Torsten 38 ; Krizsán Szilvia 39   VIAFID ORCID Logo  ; Bödör Csaba 39   VIAFID ORCID Logo  ; Stölzel Friedrich 19   VIAFID ORCID Logo  ; Onel Kenan 40   VIAFID ORCID Logo  ; Allan, James M 1   VIAFID ORCID Logo 

1  Newcastle University, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle upon Tyne, UK (GRID:grid.1006.7) (ISNI:0000 0001 0462 7212) 
2  University of Chicago, Section of Pediatric Hematology and Oncology, Chicago, USA (GRID:grid.170205.1) (ISNI:0000 0004 1936 7822) 
3  Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); Ludwig-Maximilians-Universität München, Chair of Genetic Epidemiology, IBE, Faculty of Medicine, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
4  Ludwig-Maximilians-Universität München, Chair of Genetic Epidemiology, IBE, Faculty of Medicine, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
5  College of Pharmacy, The Ohio State University, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943) 
6  Roswell Park Cancer Institute, Department of Medicine, Buffalo, USA (GRID:grid.240614.5) (ISNI:0000 0001 2181 8635) 
7  University of South Carolina, Arnold School of Public Health, Department of Epidemiology & Biostatistics, Greenville, USA (GRID:grid.254567.7) (ISNI:0000 0000 9075 106X) 
8  Department of Haematology, Freeman Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, UK (GRID:grid.415050.5) (ISNI:0000 0004 0641 3308) 
9  Department of Medical and Molecular Genetics, King’s College Medical School, London, UK (GRID:grid.415050.5) 
10  University of Oxford, Nuffield Department of Population Health, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
11  Paul O’Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, UK (GRID:grid.8756.c) (ISNI:0000 0001 2193 314X) 
12  Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK (GRID:grid.240404.6) (ISNI:0000 0001 0440 1889) 
13  Barts Cancer Institute, Queen Mary University of London, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133) 
14  Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK (GRID:grid.413631.2) (ISNI:0000 0000 9468 0801) 
15  Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK (GRID:grid.18886.3f) 
16  Newcastle University, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK (GRID:grid.1006.7) (ISNI:0000 0001 0462 7212) 
17  West Midlands Regional Genetics Laboratory, Birmingham Women’s Hospital, Birmingham, UK (GRID:grid.423077.5) (ISNI:0000 0004 0399 7598) 
18  The Rayne Institute, King’s College London, Department of Haematological Medicine, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); National Center for Tumor Diseases NCT, Partner site Dresden, Dresden, Germany (GRID:grid.461742.2); Medizinische Klinik und Poliklinik I, University Hospital Carl Gustav Carus Dresden, Technical University of Dresden, Dresden, Germany (GRID:grid.4488.0) (ISNI:0000 0001 2111 7257) 
19  Medizinische Klinik und Poliklinik I, University Hospital Carl Gustav Carus Dresden, Technical University of Dresden, Dresden, Germany (GRID:grid.4488.0) (ISNI:0000 0001 2111 7257) 
20  Newcastle University, Population Health Sciences Institute, Newcastle upon Tyne, UK (GRID:grid.1006.7) (ISNI:0000 0001 0462 7212) 
21  University Hospital Rigshospitalet, Department of Clinical Genetics, Copenhagen, Denmark (GRID:grid.475435.4) 
22  University of Bologna, Institute of Hematology “L. and A. Seràgnoli”, Bologna, Italy (GRID:grid.6292.f) (ISNI:0000 0004 1757 1758); IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy (GRID:grid.6292.f) 
23  IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy (GRID:grid.6292.f) 
24  Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain (GRID:grid.84393.35) (ISNI:0000 0001 0360 9602); CIBERONC, Instituto de Salud Carlos III, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427) 
25  Cote d’Azur University, CHU of Nice, Hematology department, Nice, France (GRID:grid.410528.a) (ISNI:0000 0001 2322 4179) 
26  Medical University of Graz, Division of Hematology, Graz, Austria (GRID:grid.11598.34) (ISNI:0000 0000 8988 2476) 
27  Università di Roma Tor Vergata, Dipartimento di Biomedicina e Prevenzione, Rome, Italy (GRID:grid.6530.0) (ISNI:0000 0001 2300 0941) 
28  Hôpital Saint-Louis, Institut Universitaire d’Hématologie, Université Paris Diderot, Paris, France (GRID:grid.6530.0) 
29  Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France (GRID:grid.410463.4) (ISNI:0000 0004 0471 8845) 
30  University College London Cancer Institute, Department of Haematology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
31  Semmewleis University, 1st Department of Internal Medicine, Budapest, Hungary (GRID:grid.83440.3b) 
32  Semmewleis University, 3rd Department of Internal Medicine, Budapest, Hungary (GRID:grid.83440.3b) 
33  Heidelberg University, Department of Hematology and Oncology, Medical Faculty Mannheim, Mannheim, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373) 
34  University of Cardiff, Department of Haematology, Cardiff, UK (GRID:grid.5600.3) (ISNI:0000 0001 0807 5670) 
35  Hematology Research Unit Helsinki, University of Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
36  Medical University of Vienna, Department of Laboratory Medicine, Vienna, Austria (GRID:grid.22937.3d) (ISNI:0000 0000 9259 8492) 
37  Department of Medical and Molecular Genetics, King’s College Medical School, London, UK (GRID:grid.22937.3d) 
38  MLL Munich Leukemia Laboratory, Munich, Germany (GRID:grid.420057.4) (ISNI:0000 0004 7553 8497) 
39  Semmelweis University, HCEMM-SE Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Budapest, Hungary (GRID:grid.11804.3c) (ISNI:0000 0001 0942 9821) 
40  Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-26551-x
ProQuest document ID
2588170002
Copyright
© The Author(s) 2021. corrected publication 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.