title: Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children.
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 p16(INK4A), 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.
authors.affiliation: 1] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Xu
authors.affiliation: 1] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Department of Pediatrics, The first affiliated hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.affiliation: Centre for Biological Sequence Analysis, The Technical University of Denmark, Kgs, Lyngby DK-2800, Denmark.
authors.forename: Rachita
authors.initials: R
authors.lastname: Yadav
authors.affiliation: Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center, Houston, Texas 77030, USA.
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Maoxiang
authors.initials: M
authors.lastname: Qian
authors.affiliation: Department of Biostatistics, Epidemiology and Health Policy Research, College of Medicine, University of Florida, Gainesville, Florida 32610, USA.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Perez-Andreu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Xujie
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, and Departments of Pathology and Pediatrics, Ohio State University College of Medicine, Columbus, Ohio 43205, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Lupo
authors.affiliation: Hartwell Center for Bioinformatics &Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Geoff
authors.initials: G
authors.lastname: Neale
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Raetz
authors.affiliation: Maine Children's Cancer Program, Scarborough, Maine 04074, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Larsen
authors.affiliation: Cook Children's Medical Center, Ft. Worth, Texas 38754, USA.
authors.forename: W Paul
authors.initials: WP
authors.lastname: Bowman
authors.affiliation: Pediatric Oncology, Cancer Institute New York University, New York City, New York 10016, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.affiliation: Pediatric Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Winick
authors.affiliation: Puma Biotechnology Inc., Los Angeles, California 90024, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: Department of Pediatrics, The Children's Obesity Clinic, Copenhagen University Hospital Holbaek, Holbaek DK-4300, Denmark.
authors.forename: Jens-Christian
authors.initials: JC
authors.lastname: Holm
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Mardis
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Fulton
authors.affiliation: 1] Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1] Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: 1] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Centre for Biological Sequence Analysis, The Technical University of Denmark, Kgs, Lyngby DK-2800, Denmark.
authors.forename: Ramneek
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, and the Institute of Clinical Medicine, Faculty of Health, University of Copenhagen, Copenhagen DK-2100, Denmark.
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
authors.affiliation: Department of Pediatrics, Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94115, USA.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: 1] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.affiliation: 1] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002648:Child; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D051379:Mice; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C503805:ARID5B protein, human; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; D014157:Transcription Factors; D051740:Ikaros Transcription Factor