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.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Jayaram
authors.initials: J
authors.lastname: Vijayakrishnan
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Marc
authors.initials: M
authors.lastname: Henrion
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Fiege
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: Miguel Inacio
authors.initials: MI
authors.lastname: da Silva Filho
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Holroyd
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Koehler
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Thomsen
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Irving
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: James M
authors.initials: JM
authors.lastname: Allan
authors.affiliation: Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom.
authors.forename: Tracy
authors.initials: T
authors.lastname: Lightfoot
authors.affiliation: Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, United Kingdom.
authors.forename: Eve
authors.initials: E
authors.lastname: Roman
authors.affiliation: Department of Paediatric and Adolescent Haematology and Oncology, Leeds General Infirmary, Leeds, United Kingdom.|Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Kinsey
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.affiliation: Paediatric and Familial Cancer, Institute of Cancer Sciences, Manchester, United Kingdom.
authors.forename: Pamela D
authors.initials: PD
authors.lastname: Thompson
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Genomic Imaging Group, Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Lewin
authors.initials: L
authors.lastname: Eisele
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.affiliation: General Paediatrics, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Mel
authors.initials: M
authors.lastname: Greaves
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
authors.affiliation: General Paediatrics, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D002648:Child; D002675:Child, Preschool; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology* / Q000235:genetics*; D015995:Prevalence; D012307:Risk Factors; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16