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; Jun J. Yang

doi:10.1038/s41467-019-13069-6

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. HungerMartin Schrappe, Mary V. Relling, Martin Stanulla, Mignon L. Loh, Richard S. Houlston, Jun J. Yang

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

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.

Original language	English
Article number	5348
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13069-6
State	Published - 1 Dec 2019
Externally published	Yes

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Vijayakrishnan, J., Qian, M., Studd, J. B., Yang, W., Kinnersley, B., Law, P. J., Broderick, P., Raetz, E. A., Allan, J., Pui, C. H., Vora, A., Evans, W. E., Moorman, A., Yeoh, A., Yang, W., Li, C., Bartram, C. R., Mullighan, C. G., Zimmerman, M., ... Yang, J. J. (2019). Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk. Nature Communications, 10(1), Article 5348. https://doi.org/10.1038/s41467-019-13069-6

@article{53823d22db124b2288dfdf6d4dbe7f94,

title = "Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk",

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.",

author = "Jayaram Vijayakrishnan and Maoxiang Qian and Studd, {James B.} and Wenjian Yang and Ben Kinnersley and Law, {Philip J.} and Peter Broderick and Raetz, {Elizabeth A.} and James Allan and Pui, {Ching Hon} and Ajay Vora and Evans, {William E.} and Anthony Moorman and Allen Yeoh and Wentao Yang and Chunliang Li and Bartram, {Claus R.} and Mullighan, {Charles G.} and Martin Zimmerman and Hunger, {Stephen P.} and Martin Schrappe and Relling, {Mary V.} and Martin Stanulla and Loh, {Mignon L.} and Houlston, {Richard S.} and Yang, {Jun J.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-13069-6",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

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Vijayakrishnan, J, Qian, M, Studd, JB, Yang, W, Kinnersley, B, Law, PJ, Broderick, P, Raetz, EA, Allan, J, Pui, CH, Vora, A, Evans, WE, Moorman, A, Yeoh, A, Yang, W, Li, C, Bartram, CR, Mullighan, CG, Zimmerman, M, Hunger, SP, Schrappe, M, Relling, MV, Stanulla, M, Loh, ML, Houlston, RS & Yang, JJ 2019, 'Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk', Nature Communications, vol. 10, no. 1, 5348. https://doi.org/10.1038/s41467-019-13069-6

TY - JOUR

T1 - Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk

AU - Vijayakrishnan, Jayaram

AU - Qian, Maoxiang

AU - Studd, James B.

AU - Yang, Wenjian

AU - Kinnersley, Ben

AU - Law, Philip J.

AU - Broderick, Peter

AU - Raetz, Elizabeth A.

AU - Allan, James

AU - Pui, Ching Hon

AU - Vora, Ajay

AU - Evans, William E.

AU - Moorman, Anthony

AU - Yeoh, Allen

AU - Yang, Wentao

AU - Li, Chunliang

AU - Bartram, Claus R.

AU - Mullighan, Charles G.

AU - Zimmerman, Martin

AU - Hunger, Stephen P.

AU - Schrappe, Martin

AU - Relling, Mary V.

AU - Stanulla, Martin

AU - Loh, Mignon L.

AU - Houlston, Richard S.

AU - Yang, Jun J.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-019-13069-6

DO - 10.1038/s41467-019-13069-6

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AN - SCOPUS:85075556274

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5348

ER -

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

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