title: A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology.
abstract: Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility (Pcombined=3.32 × 10(-15), OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a cis-eQTL for CDKN2B, with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating CDKN2B expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining CDKN2A exon 3 usage (P=0.01). These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology.
authors: Department of Pediatrics, University of Chicago, 900 East 57th Street, Room 5140, MC 4060, Chicago, Illinois 60637, USA.
authors: Eric A
authors: EA
authors: Hungate
authors: Committee on Cancer Biology, University of Chicago, Chicago, Illinois 60637, USA.
authors: Sapana R
authors: SR
authors: Vora
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.|The Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, The Netherlands.
authors: Eric R
authors: ER
authors: Gamazon
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Takaya
authors: T
authors: Moriyama
authors: Committee on Cancer Biology, University of Chicago, Chicago, Illinois 60637, USA.
authors: Timothy
authors: T
authors: Best
authors: Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, Illinois 60637, USA.
authors: Imge
authors: I
authors: Hulur
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors: Younghee
authors: Y
authors: Lee
authors: Faculty of Medicine and Health, Information Based Medicine, Hunter Medical Research Institute, School of Biomedical Sciences and Pharmacy, University of Newcastle, New Lambton, New South Wales 2305, Australia.
authors: Tiffany-Jane
authors: TJ
authors: Evans
authors: Institute of Clinical Molecular Biology, Christian-Albrechts University, Kiel 24118, Germany.
authors: Eva
authors: http://orcid.org/0000-0003-2914-3382
authors: E
authors: Ellinghaus
authors: Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel 24105, Germany.
authors: Martin
authors: M
authors: Stanulla
authors: INSERM U1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Epidemiology of Childhood and Adolescent Cancers Team (EPICEA), Villejuif 94807, France.|UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Paris-Descartes University, Paris 75270, France.
authors: Jéremie
authors: J
authors: Rudant
authors: INSERM U1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Epidemiology of Childhood and Adolescent Cancers Team (EPICEA), Villejuif 94807, France.|UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Paris-Descartes University, Paris 75270, France.
authors: Laurent
authors: L
authors: Orsi
authors: INSERM U1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Epidemiology of Childhood and Adolescent Cancers Team (EPICEA), Villejuif 94807, France.|UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Paris-Descartes University, Paris 75270, France.|French National Registry of Childhood Hematopoietic Malignancies (RNHE), Villejuif 94807, France.
authors: Jacqueline
authors: J
authors: Clavel
authors: Telethon Kids Institute, University of Western Australia, Crawley, Western Australia 6872, Australia.
authors: Elizabeth
authors: E
authors: Milne
authors: Faculty of Medicine and Health, Information Based Medicine, Hunter Medical Research Institute, School of Biomedical Sciences and Pharmacy, University of Newcastle, New Lambton, New South Wales 2305, Australia.|Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales 2305, Australia.
authors: Rodney J
authors: RJ
authors: Scott
authors: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Ching-Hon
authors: CH
authors: Pui
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors: Nancy J
authors: NJ
authors: Cox
authors: Department of Pediatrics, University of California-San Francisco, San Francisco, California 94143, USA.
authors: Mignon L
authors: ML
authors: Loh
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Jun J
authors: http://orcid.org/0000-0002-0770-9659
authors: JJ
authors: Yang
authors: Department of Pediatrics, University of Chicago, 900 East 57th Street, Room 5140, MC 4060, Chicago, Illinois 60637, USA.
authors: Andrew D
authors: AD
authors: Skol
authors: Department of Pediatrics, University of Chicago, 900 East 57th Street, Room 5140, MC 4060, Chicago, Illinois 60637, USA.
authors: Kenan
authors: K
authors: Onel
mesh_terms: D001741:Black or African American / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15