A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology

Eric A. Hungate, Sapana R. Vora, Eric R. Gamazon, Takaya Moriyama, Timothy Best, Imge Hulur, Younghee Lee, Tiffany-Jane Evans, Eva Ellinghaus, Martin Stanulla, Jéremie Rudant, Laurent Orsi, Jacqueline Clavel, Elizabeth Milne, Rodney J. Scott, Ching-Hon Pui, Nancy J. Cox, Mignon L. Loh, Jun J. Yang, Andrew D. Skol and Kenan Onel ()
Additional contact information
Eric A. Hungate: University of Chicago, 900 East 57th Street, Room 5140, MC 4060, Chicago, Illinois 60637, USA
Sapana R. Vora: Committee on Cancer Biology, University of Chicago, Chicago, Illinois 60637, USA
Eric R. Gamazon: Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
Takaya Moriyama: St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA
Timothy Best: Committee on Cancer Biology, University of Chicago, Chicago, Illinois 60637, USA
Imge Hulur: Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, Illinois 60637, USA
Younghee Lee: Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
Tiffany-Jane Evans: 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
Eva Ellinghaus: Institute of Clinical Molecular Biology, Christian-Albrechts University
Martin Stanulla: University Hospital Schleswig-Holstein
Jéremie Rudant: INSERM U1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Epidemiology of Childhood and Adolescent Cancers Team (EPICEA)
Laurent Orsi: INSERM U1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Epidemiology of Childhood and Adolescent Cancers Team (EPICEA)
Jacqueline Clavel: INSERM U1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Epidemiology of Childhood and Adolescent Cancers Team (EPICEA)
Elizabeth Milne: Telethon Kids Institute, University of Western Australia
Rodney J. Scott: 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
Ching-Hon Pui: St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA
Nancy J. Cox: Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
Mignon L. Loh: University of California–San Francisco, San Francisco, California 94143, USA
Jun J. Yang: St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA
Andrew D. Skol: University of Chicago, 900 East 57th Street, Room 5140, MC 4060, Chicago, Illinois 60637, USA
Kenan Onel: University of Chicago, 900 East 57th Street, Room 5140, MC 4060, Chicago, Illinois 60637, USA

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10635

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