Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk

Jayaram Vijayakrishnan, Maoxiang Qian, James B. Studd, Wenjian Yang, Ben Kinnersley, Philip J. Law, Peter Broderick, Elizabeth A. Raetz, James Allan, Ching-Hon Pui, Ajay Vora, William E. Evans, Anthony Moorman, Allen Yeoh, Wentao Yang, Chunliang Li, Claus R. Bartram, Charles G. Mullighan, Martin Zimmerman, Stephen P. Hunger, Martin Schrappe, Mary V. Relling, Martin Stanulla, Mignon L. Loh, Richard S. Houlston () and Jun J. Yang ()
Additional contact information
Jayaram Vijayakrishnan: The Institute of Cancer Research
Maoxiang Qian: St. Jude Children’s Research Hospital
James B. Studd: The Institute of Cancer Research
Wenjian Yang: St. Jude Children’s Research Hospital
Ben Kinnersley: The Institute of Cancer Research
Philip J. Law: The Institute of Cancer Research
Peter Broderick: The Institute of Cancer Research
Elizabeth A. Raetz: New York University Langone Health
James Allan: Newcastle University
Ching-Hon Pui: St. Jude Children’s Research Hospital
Ajay Vora: Great Ormond Hospital
William E. Evans: St. Jude Children’s Research Hospital
Anthony Moorman: Newcastle University
Allen Yeoh: National University of Singapore
Wentao Yang: St. Jude Children’s Research Hospital
Chunliang Li: St. Jude Children’s Research Hospital
Claus R. Bartram: University Hospital
Charles G. Mullighan: St. Jude Children’s Research Hospital
Martin Zimmerman: Hannover Medical School
Stephen P. Hunger: Children’s Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania
Martin Schrappe: University Medical Centre Schleswig-Holstein
Mary V. Relling: St. Jude Children’s Research Hospital
Martin Stanulla: Hannover Medical School
Mignon L. Loh: University of California San Francisco
Richard S. Houlston: The Institute of Cancer Research
Jun J. Yang: St. Jude Children’s Research Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13069-6

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