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Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children

Author

Listed:
  • Heng Xu

    (St. Jude Children’s Research Hospital
    National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, and Cancer Center, West China Hospital, Sichuan University)

  • Hui Zhang

    (St. Jude Children’s Research Hospital
    The first affiliated hospital of Guangzhou Medical University)

  • Wenjian Yang

    (St. Jude Children’s Research Hospital)

  • Rachita Yadav

    (Centre for Biological Sequence Analysis, The Technical University of Denmark, Kgs)

  • Alanna C. Morrison

    (Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center)

  • Maoxiang Qian

    (St. Jude Children’s Research Hospital)

  • Meenakshi Devidas

    (Epidemiology and Health Policy Research, College of Medicine, University of Florida)

  • Yu Liu

    (St. Jude Children’s Research Hospital)

  • Virginia Perez-Andreu

    (St. Jude Children’s Research Hospital)

  • Xujie Zhao

    (St. Jude Children’s Research Hospital)

  • Julie M. Gastier-Foster

    (Nationwide Children’s Hospital, Ohio State University College of Medicine)

  • Philip J. Lupo

    (Texas Children's Cancer Center, Baylor College of Medicine)

  • Geoff Neale

    (Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children’s Research Hospital)

  • Elizabeth Raetz

    (Huntsman Cancer Institute, The University of Utah)

  • Eric Larsen

    (Maine Children’s Cancer Program)

  • W. Paul Bowman

    (Cook Children's Medical Center)

  • William L. Carroll

    (Pediatric Oncology, Cancer Institute New York University)

  • Naomi Winick

    (Pediatric Hematology/Oncology, University of Texas Southwestern Medical Center)

  • Richard Williams

    (Puma Biotechnology Inc.)

  • Torben Hansen

    (The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Jens-Christian Holm

    (The Children’s Obesity Clinic, Copenhagen University Hospital Holbaek)

  • Elaine Mardis

    (McDonnell Genome Institute, Washington University School of Medicine)

  • Robert Fulton

    (McDonnell Genome Institute, Washington University School of Medicine)

  • Ching-Hon Pui

    (Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital
    St. Jude Children’s Research Hospital)

  • Jinghui Zhang

    (St. Jude Children’s Research Hospital)

  • Charles G. Mullighan

    (Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital
    St. Jude Children’s Research Hospital)

  • William E. Evans

    (St. Jude Children’s Research Hospital
    Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital)

  • Stephen P. Hunger

    (Children’s Hospital of Philadelphia)

  • Ramneek Gupta

    (Centre for Biological Sequence Analysis, The Technical University of Denmark, Kgs)

  • Kjeld Schmiegelow

    (The Juliane Marie Centre, The University Hospital Rigshospitalet, and the Institute of Clinical Medicine, Faculty of Health, University of Copenhagen)

  • Mignon L. Loh

    (Benioff Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco)

  • Mary V. Relling

    (St. Jude Children’s Research Hospital
    Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital)

  • Jun J. Yang

    (St. Jude Children’s Research Hospital
    Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital)

Abstract

There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 × 10−23, odds ratio=2.23). Functional studies indicate that this hypomorphic variant results in reduced tumour suppressor function of p16INK4A, increases the susceptibility to leukaemic transformation of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A–CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation on ALL risk, highlighting the important and complex roles of CDKN2A–CDKN2B tumour suppressors in leukaemogenesis.

Suggested Citation

  • Heng Xu & Hui Zhang & Wenjian Yang & Rachita Yadav & Alanna C. Morrison & Maoxiang Qian & Meenakshi Devidas & Yu Liu & Virginia Perez-Andreu & Xujie Zhao & Julie M. Gastier-Foster & Philip J. Lupo & G, 2015. "Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children," Nature Communications, Nature, vol. 6(1), pages 1-7, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8553
    DOI: 10.1038/ncomms8553
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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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