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The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A

Lookup NU author(s): Professor Anthony MoormanORCiD, Professor Julie Irving, Professor James Allan, Professor Christine Harrison FRCPath FMedSci



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio = 2.42, P = 3.45 x 10(-19)). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the CDKN2A transcript suggesting the functional effect of p. Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm.

Publication metadata

Author(s): Vijayakrishnan J, Henrion M, Moorman AV, Fiege B, Kumar R, da Silva MI, Holroyd A, Koehler R, Thomsen H, Irving JA, Allan JM, Lightfoot T, Roman E, Kinsey SE, Sheridan E, Thompson PD, Hoffmann P, Nothen MM, Muhleisen TW, Eisele L, Bartram CR, Schrappe M, Greaves M, Hemminki K, Harrison CJ, Stanulla M, Houlston RS

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2015

Volume: 5

Online publication date: 14/10/2015

Acceptance date: 12/08/2015

Date deposited: 05/11/2015

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group


DOI: 10.1038/srep15065


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Funder referenceFunder name
Heinz Nixdord Foundation
Children with Cancer
Deutsche Krebshilfe
German Center of Neurodegenerative Disorders, Bonn
Leukaemia Lymphoma Research (UK)
Tumorzentrum Heidelberg-Mannheim
C1298/A8362Cancer Research UK (Bobby Moore Fund)