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

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, Geoff Neale, Elizabeth Raetz, Eric Larsen, W. Paul Bowman, William L. Carroll, Naomi Winick, Richard Williams, Torben Hansen, Jens-Christian Holm, Elaine Mardis, Robert Fulton, Ching-Hon Pui, Jinghui Zhang, Charles G. Mullighan, William E. Evans, Stephen P. Hunger, Ramneek Gupta, Kjeld Schmiegelow, Mignon L. Loh, Mary V. Relling and Jun J. Yang ()
Additional contact information
Heng Xu: St. Jude Children’s Research Hospital
Hui Zhang: St. Jude Children’s Research Hospital
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
Jinghui Zhang: St. Jude Children’s Research Hospital
Charles G. Mullighan: Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital
William E. Evans: 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
Jun J. Yang: St. Jude Children’s Research Hospital

Nature Communications, 2015, vol. 6, issue 1, 1-7

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8553

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