机构：[1]Department of Pharmaceutical Sciences, St.Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA[2]Department of Laboratory Medicine, National KeyLaboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China四川大学华西医院[3]Department of Pediatrics, The first affiliated hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China[4]Centre for Biological Sequence Analysis,The Technical University of Denmark, Kgs, Lyngby DK-2800, Denmark[5]Department of Epidemiology, Human Genetics, and Environmental Sciences, School of PublicHealth, University of Texas Health Science Center, Houston, Texas 77030, USA[6]Department of Biostatistics, Epidemiology and Health Policy Research, College ofMedicine, University of Florida, Gainesville, Florida 32610, USA[7]Department of Computational Biology, St.Jude Children’s Research Hospital, Memphis, Tennessee38105, USA[8]Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, and Departments of Pathology and Pediatrics, Ohio State UniversityCollege of Medicine, Columbus, Ohio 43205, USA[9]Department of Pediatrics, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA[10]Hartwell Center for Bioinformatics & Biotechnology, St.Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA[11]Huntsman Cancer Institute, TheUniversity of Utah, Salt Lake City, Utah 84112, USA[12]Maine Children’s Cancer Program, Scarborough, Maine 04074, USA[13]Cook Children’s Medical Center, Ft.Worth,Texas 38754, USA[14]Pediatric Oncology, Cancer Institute New York University, New York City, New York 10016, USA[15]Pediatric Hematology/Oncology, University ofTexas Southwestern Medical Center, Dallas, Texas 75235, USA[16]Puma Biotechnology Inc,Los Angeles, California 90024, USA[17]The Novo Nordisk Foundation Centerfor Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark[18]Department of Pediatrics, TheChildren’s Obesity Clinic, Copenhagen University Hospital Holbaek, Holbaek DK-4300, Denmark[19]McDonnell Genome Institute, Washington University School ofMedicine, St Louis, Missouri 63108, USA[20]Hematological Malignancies Program, Comprehensive Cancer Center, St.Jude Children’s Research Hospital, Memphis,Tennessee 38105, USA[21]Department of Oncology,St.Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA[22]Department of Pathology, St.Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA[23]Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia,Philadelphia, Pennsylvania 19104, USA[24]Department of Paediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, and theInstitute of Clinical Medicine, Faculty of Health, University of Copenhagen, Copenhagen DK-2100, Denmark[25]Department of Pediatrics, Benioff Children’s Hospital andthe Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94115, USA
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.
基金：
This work was supported by the National Institutes of Health (grant
numbers CA156449, CA21765, CA36401, CA98543, CA114766, CA98413, CA140729,
CA176063, GM097119 and GM92666, HHSN261200800001E), the American Lebanese
Syrian Associated Charities (ALSAC), the Danish Council for Strategic Research
(TARGET (0603-00484B), BIOCHILD (0603-00457B)), the Region Zealand Health
Scientific Research Foundation, Danish National Research Foundation, Danish Childhood Cancer Foundation, and Swedish Childhood Cancer Foundation. The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study
supported by the National Heart, Lung, and Blood Institute contracts
(HHSN268201100005C, HHSN268201100006C, HHSN268201100007C,
HHSN268201100008C, HHSN268201100009C, HHSN268201100010C,
HHSN268201100011C and HHSN268201100012C). Funding support for ‘Building on
GWAS for NHLBI-diseases: the U.S. CHARGE consortium’ was provided by the NIH
through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419)
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2015]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2023]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Department of Pharmaceutical Sciences, St.Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA[2]Department of Laboratory Medicine, National KeyLaboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Pharmaceutical Sciences, St.Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA[20]Hematological Malignancies Program, Comprehensive Cancer Center, St.Jude Children’s Research Hospital, Memphis,Tennessee 38105, USA
推荐引用方式(GB/T 7714)：
Heng Xu,Hui Zhang,Wenjian Yang,et al.Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children.[J].Nature communications.2015,6:7553.doi:10.1038/ncomms8553.
APA：
Heng Xu,Hui Zhang,Wenjian Yang,Rachita Yadav,Alanna C. Morrison...&Jun J. Yang.(2015).Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children..Nature communications,6,
MLA：
Heng Xu,et al."Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children.".Nature communications 6.(2015):7553
综合性期刊