@article{53c72fdf9bf4427fbbaac52c6bc673c3,
title = "The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A",
abstract = "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× 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.",
author = "Jayaram Vijayakrishnan and Marc Henrion and Moorman, {Anthony V.} and Bettina Fiege and Rajiv Kumar and {Inacio Da Silva Filho}, Miguel and Amy Holroyd and Rolf Koehler and Hauke Thomsen and Irving, {Julie A.} and Allan, {James M.} and Tracy Lightfoot and Eve Roman and Kinsey, {Sally E.} and Eamonn Sheridan and Thompson, {Pamela D.} and Per Hoffmann and N{\"o}then, {Markus M.} and M{\"u}hleisen, {Thomas W.} and Lewin Eisele and Bartram, {Claus R.} and Martin Schrappe and Mel Greaves and Kari Hemminki and Harrison, {Christine J.} and Martin Stanulla and Houlston, {Richard S.}",
note = "Funding Information: Leukaemia Lymphoma Research (UK) provided principal funding for the study. Support from Cancer Research UK (C1298/A8362, supported by the Bobby Moore Fund) is also acknowledged. The study made use of genotyping data from the Wellcome Trust Case Control Study. The study made use of genotyping data on the 1958 Birth Cohort. We are grateful to S. Richards and J. Burrett (Clinical Trials Service Unit, Oxford) and L. Chilton (Leukaemia Research Cytogenetics Group, Northern Institute of Cancer Research, Newcastle Univ.), J. Simpson (Univ. York), P. Thomson and A. Hussain (Cancer Immunogenetics, School of Cancer Sciences, Univ. Manchester) for assistance with data harmonisation. We thank the Leukaemia Lymphoma Research (LLR), Childhood Cancer Leukaemia Group (CCLG) and Childhood Leukaemia Cell Bank for access to ALL trial samples. We are grateful to the UK Cancer Cytogenetics Group (UKCCG) for data collection and provision of samples. P. Thompson (Paediatric and Familial Cancer, Institute of Cancer Sciences, The University of Manchester) is funded by Children with Cancer. Genotyping of German cases and controls was partly covered by funding from Tumorzentrum Heidelberg-Mannheim and Deutsche Krebshilfe. We are grateful to all the study subjects for their participation and their clinicians who contributed to the blood sample and data collection. The Heinz Nixdord Foundation supported the genotyping of Illumina HumanOmni-1 Quad BeadChips of the HNR subjects and was financed by German Center of Neurodegenerative Disorders, Bonn. The authors are grateful to investigators who contributed to this dataset and to all subjects and clinicians for their participation.",
year = "2015",
month = oct,
day = "14",
doi = "10.1038/srep15065",
language = "English (US)",
volume = "5",
journal = "Scientific reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
}