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

Author

Listed:
  • 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
    The Academic Medical Center, University of Amsterdam)

  • 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)
    UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Paris-Descartes University)

  • Laurent Orsi

    (INSERM U1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Epidemiology of Childhood and Adolescent Cancers Team (EPICEA)
    UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Paris-Descartes University)

  • Jacqueline Clavel

    (INSERM U1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Epidemiology of Childhood and Adolescent Cancers Team (EPICEA)
    UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Paris-Descartes University
    French National Registry of Childhood Hematopoietic Malignancies (RNHE))

  • 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
    Pathology North, John Hunter Hospital, Newcastle, 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)

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.

Suggested Citation

  • 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 , 2016. "A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10635
    DOI: 10.1038/ncomms10635
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    Cited by:

    1. Kashi Raj Bhattarai & Robert J. Mobley & Kelly R. Barnett & Daniel C. Ferguson & Baranda S. Hansen & Jonathan D. Diedrich & Brennan P. Bergeron & Satoshi Yoshimura & Wenjian Yang & Kristine R. Crews &, 2024. "Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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