Abstract

There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10−8), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10−8) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10−8), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10−8). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.

Details

Title
Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk
Author
Jayaram Vijayakrishnan 1   VIAFID ORCID Logo  ; Qian, Maoxiang 2 ; Studd, James B 1   VIAFID ORCID Logo  ; Yang, Wenjian 3 ; Kinnersley, Ben 1   VIAFID ORCID Logo  ; Law, Philip J 1   VIAFID ORCID Logo  ; Broderick, Peter 1   VIAFID ORCID Logo  ; Raetz, Elizabeth A 4 ; Allan, James 5 ; Ching-Hon Pui 6   VIAFID ORCID Logo  ; Vora, Ajay 7 ; Evans, William E 8   VIAFID ORCID Logo  ; Moorman, Anthony 9 ; Yeoh, Allen 10 ; Yang, Wentao 3 ; Li, Chunliang 11   VIAFID ORCID Logo  ; Bartram, Claus R 12 ; Mullighan, Charles G 13   VIAFID ORCID Logo  ; Zimmerman, Martin 14 ; Hunger, Stephen P 15 ; Schrappe, Martin 16 ; Relling, Mary V 8 ; Stanulla, Martin 14 ; Loh, Mignon L 17 ; Houlston, Richard S 1   VIAFID ORCID Logo  ; Yang, Jun J 18   VIAFID ORCID Logo 

1  Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK 
2  Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; Children’s Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China 
3  Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA 
4  Division of Pediatric Hematology and Oncology, New York University Langone Health, New York, New York, USA 
5  Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK 
6  Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; Hematological Malignancies Program, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA 
7  Great Ormond Hospital, London, UK 
8  Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; Hematological Malignancies Program, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA 
9  Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK 
10  Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; VIVA–University Children’s Cancer Centre, Khoo Teck Puat–National University Children’s Medical Institute, National University Hospital, National University Health System, Singapore, Singapore 
11  Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA 
12  Institute of Human Genetics, University Hospital, Heidelberg, Germany 
13  Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; Hematological Malignancies Program, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA 
14  Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany 
15  Department of Paediatrics and Centre for Childhood Cancer Research, Children’s Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA 
16  Department of Paediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany 
17  Department of Pediatrics, Benioff Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA 
18  Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; Hematological Malignancies Program, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA 
Pages
1-9
Publication year
2019
Publication date
Nov 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-13069-6
ProQuest document ID
2317938629
Copyright
© 2019. 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.