ArticleNature communications2015
Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children.
Registry-linked trialOpen access · goldAbstract read
In one paragraph
Article in Nature communications, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00137111 (Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia), which is not on this map. Cited by 63 papers, 5 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
63citing papers in PubMed, 5 pooled it
8.6field-weighted citation impact, top 2% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Who cites it
63 citing papers in PubMed, 5 syntheses or guidelines pooled it, 81 citations in OpenAlex.
- Pooled it
- Association of the independent polymorphisms in CDKN2A with susceptibility of acute lymphoblastic leukemia.Bioscience reports · 2018Pooled it
- Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose.Oncotarget · 2017Pooled it
- Association Between PIP4K2A Polymorphisms and Acute Lymphoblastic Leukemia Susceptibility.Medicine · 2016Pooled it
- NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.Nature genetics · 2016Pooled it
- Association of GATA3 Polymorphisms With Minimal Residual Disease and Relapse Risk in Childhood Acute Lymphoblastic Leukemia.Journal of the National Cancer Institute · 2021Trial
- Characterization of Genetic Etiologic Factors for Pediatric Acute Lymphoblastic Leukemia in Large Childhood Cancer Survivorship Cohorts.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2026Article
- A Greek Case-Control Replication Study ofGenes · 2026Article
- Review
- Pathogenic CDKN2A germline variants are rare in a cohort of unselected pancreatic cancer patients from Pakistan.Familial cancer · 2025Article
- Article
- Review
- Allelic expression imbalance of CDKN2A variants in childhood acute lymphoblastic leukemia.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- A comprehensive consolidation of data on the connection between CDKN2A polymorphisms and the susceptibility to childhood acute lymphoblastic leukemia.Hematology, transfusion and cell therapy · 2024Review
- Article
- Acute lymphoblastic leukaemia.Nature reviews. Disease primers · 2024Review
- Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.Nature communications · 2024Article
- Constitutively active CaMKII Drives B lineage acute lymphoblastic leukemia/lymphoma in tp53 mutant zebrafish.PLoS genetics · 2023Article
- Association of CDKN2A/B mutations, PD-1, and PD-L1 with the risk of acute lymphoblastic leukemia in children.Journal of cancer research and clinical oncology · 2023Article
- Genes of Predisposition to Childhood Beta-Cell Acute Lymphoblastic Leukemia in the Kazakh Population.Asian Pacific journal of cancer prevention : APJCP · 2023Article
3 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
33 authors at 18 institutions in 3 countries.
Heng Xu1] 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.
Hui Zhang1] 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.
Wenjian YangDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Rachita YadavCentre for Biological Sequence Analysis, The Technical University of Denmark, Kgs, Lyngby DK-2800, Denmark.
Alanna C MorrisonDepartment of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center, Houston, Texas 77030, USA.
Maoxiang QianDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Meenakshi DevidasDepartment of Biostatistics, Epidemiology and Health Policy Research, College of Medicine, University of Florida, Gainesville, Florida 32610, USA.
Yu LiuDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Virginia Perez-AndreuDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Xujie ZhaoDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Julie M Gastier-FosterDepartment 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.
Philip J LupoDepartment of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Geoff NealeHartwell Center for Bioinformatics &Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Elizabeth RaetzHuntsman Cancer Institute, The University of Utah, Salt Lake City, Utah 84112, USA.
Eric LarsenMaine Children's Cancer Program, Scarborough, Maine 04074, USA.
W Paul BowmanCook Children's Medical Center, Ft. Worth, Texas 38754, USA.
William L CarrollPediatric Oncology, Cancer Institute New York University, New York City, New York 10016, USA.
Naomi WinickPediatric Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
Richard WilliamsPuma Biotechnology Inc., Los Angeles, California 90024, USA.
Torben HansenThe Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
Jens-Christian HolmDepartment of Pediatrics, The Children's Obesity Clinic, Copenhagen University Hospital Holbaek, Holbaek DK-4300, Denmark.
Elaine MardisMcDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.
Robert FultonMcDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA.
Ching-Hon Pui1] 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.
Jinghui ZhangDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Charles G Mullighan1] 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.
William E Evans1] 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.
Stephen P HungerDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Ramneek GuptaCentre for Biological Sequence Analysis, The Technical University of Denmark, Kgs, Lyngby DK-2800, Denmark.
Kjeld SchmiegelowDepartment 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.
Mignon L LohDepartment 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.
Mary V Relling1] 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.
Jun J Yang1] 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.
St. Jude Children's Research Hospital · USJames S. McDonnell Foundation · USTechnical University of Denmark · DKBaylor College of Medicine · USChildren's Hospital of Philadelphia · USCook Children's Medical Center · USHolbæk Sygehus · DKHuntsman Cancer Institute · USNationwide Children's Hospital · USNew England Cancer Specialists · USNew York University · USNovo Nordisk Foundation · DKPuma Biotechnology (United States) · USRigshospitalet · DKThe University of Texas Health Science Center at Houston · USThe University of Texas Southwestern Medical Center · USUCSF Benioff Children's Hospital · USUniversity of Florida · US
Funding
NCTN BIQSFP ANBL1531 (NRT)U10CA180886 · NCI · PUBLIC HEALTH INSTITUTE · PI Douglas S. Hawkins · 2014 to 2026
$390.6MCOG FOREIGN ACCRUALU10CA098543 · NCI · NATIONAL CHILDHOOD CANCER FOUNDATION · PI ADAMSON, PETER C. · 2003 to 2013
$335.5MViral Vector Technology (VVTSR)P30CA021765 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI CHARLES ROBERTS · 1985 to 2026
$166.9MChildren's Oncology Group Statistics &Data Center GrantU10CA098413 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI DEVIDAS, MEENAKSHI · 2003 to 2013
$67.5MBuilding on GWAS for NHLBI-disease: the CHARGE consortiumRC2HL102419 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI BOERWINKLE, ERIC A. · 2009 to 2010
$27.6MSupport for Human Specimen Banking in NCI-Supported Cancer Clinical TrialsU24CA114766 · NCI · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · PI RAMIREZ MILAN, NILSA DEL CARMEN · 2005 to 2014
$14.5MPHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL)R37CA036401 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI EVANS, WILLIAM E · 1987 to 2014
$9.7MPAARK4Kids-Pharmacogenomics of Anticancer Agents Research in ChildrenU01GM092666 · NIGMS · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI RELLING, MARY V · 2010 to 2014
$8.9MDrug Resistant Pathways in Relapsed Acute Lymphoblastic Leukemia(ALL)R01CA140729 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI CARROLL, WILLIAM L. · 2010 to 2020
$4.8MPharmacogenomics of Childhood Leukemia ALLR01CA036401 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI EVANS, WILLIAM E · 1985 to 2019
$3.6MNEXT GENERATION SEQUENCING ADD-ON-PHARMACOGENOMICS RESEARCH NETWROK (PGRN)U01GM097119 · NIGMS · WASHINGTON UNIVERSITY · PI MARDIS, ELAINE R · 2010 to 2014
$2.6MARID5B and disparities of childhood leukemiaU01CA176063 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI YANG, JUN J. · 2014 to 2018
$2.4MCCR NIH HHS HHSN261200800001CNCI NIH HHS HHSN261200800001ENCI NIH HHS P30 CA021765NCI NIH HHS R01 CA036401NCI NIH HHS R01 CA140729NCI NIH HHS R37 CA036401NCI NIH HHS RC4 CA156449NCI NIH HHS U01 CA176063NCI NIH HHS U10 CA098413NCI NIH HHS U10 CA098543NCI NIH HHS U10 CA180886NCI NIH HHS U24 CA114766NHLBI NIH HHS 5RC2HL102419NHLBI NIH HHS HHSN268201100005CNHLBI NIH HHS HHSN268201100005GNHLBI NIH HHS HHSN268201100005INHLBI NIH HHS HHSN268201100006CNHLBI NIH HHS HHSN268201100007CNHLBI NIH HHS HHSN268201100007INHLBI NIH HHS HHSN268201100008CNHLBI NIH HHS HHSN268201100008INHLBI NIH HHS HHSN268201100009CNHLBI NIH HHS HHSN268201100009INHLBI NIH HHS HHSN268201100010CNHLBI NIH HHS HHSN268201100011CNHLBI NIH HHS HHSN268201100011INHLBI NIH HHS HHSN268201100012CNHLBI NIH HHS RC2 HL102419NIGMS NIH HHS U01 GM092666NIGMS NIH HHS U01 GM097119
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.
Indexed as
AnimalsCase-Control StudiesChildCyclin-Dependent Kinase Inhibitor p15Cyclin-Dependent Kinase Inhibitor p16DNA-Binding ProteinsGenetic Predisposition to DiseaseGenetic VariationGenome-Wide Association StudyGenotypeGerm-Line MutationHEK293 CellsHematopoietic Stem CellsHumansIkaros Transcription FactorMiceARID5B protein, humanCDKN2B protein, humanCyclin-Dependent Kinase Inhibitor p15Cyclin-Dependent Kinase Inhibitor p16DNA-Binding ProteinsIkaros Transcription FactorIKZF1 protein, humanTranscription Factors
Identifiers
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LicenceCC BY
Read underepoch 390
Registered trials
NCT00137111ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.