title: A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults.
abstract: Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms (SNPs) in 308 AYA ALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10(-8) in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10(-10)) and rs3781093, OR, 1.73 (P = 3.2 × 10(-9)). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10(-11)). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.
authors.affiliation: Department of Pharmaceutical Sciences and.
authors.forename: Virginia
authors.initials: V
authors.lastname: Perez-Andreu
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Roberts
authors.affiliation: Department of Pharmaceutical Sciences and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China;
authors.forename: Heng
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutical Sciences and.
authors.forename: Colton
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Pharmaceutical Sciences and.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences and.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.affiliation: University of New Mexico Cancer Center, Albuquerque, NM;
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Debbie
authors.initials: D
authors.lastname: Payne-Turner
authors.affiliation: Department of Biostatistics, Colleges of Medicine, Public Health & Health Professions, University of Florida, Gainesville, FL;
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM;
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Cheng
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY;
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.affiliation: Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH;
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Raetz
authors.affiliation: The Ohio State University, Nationwide Children's Hospital, Columbus, OH;
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH;
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH;
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH;
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Alliance of Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester;
authors.forename: Jessica
authors.initials: J
authors.lastname: Kohlschmidt
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL;
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
authors.affiliation: Section of Molecular Hematology & Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Department of Medicine (Oncology), Albert Einstein College of Medicine, Yeshiva University, New York, NY;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.affiliation: Rambam Medical Center, Haifa, Israel;
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.affiliation: Hematologic Malignancies Program, Hematology-Oncology Division, University of Pennsylvania, Philadelphia, PA;
authors.forename: Selina M
authors.initials: SM
authors.lastname: Luger
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Laboratory of Experimental Immunology, National Cancer Institute, Frederick, MD;
authors.forename: Michael
authors.initials: M
authors.lastname: Dean
authors.affiliation: Department of Bioengineering & Therapeutic Science and Department of Medicine, University of California, San Francisco, San Francisco, CA;
authors.forename: Esteban G
authors.initials: EG
authors.lastname: Burchard
authors.affiliation: Department of Bioengineering & Therapeutic Science and Department of Medicine, University of California, San Francisco, San Francisco, CA;
authors.forename: Dara G
authors.initials: DG
authors.lastname: Torgerson
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Feng
authors.initials: F
authors.lastname: Yue
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Yanli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.affiliation: Department of Pharmaceutical Sciences and.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.affiliation: Department of Pharmaceutical Sciences and.
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Office of Cancer Genomics, National Cancer Institute, Bethesda, MD;
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Gerhard
authors.affiliation: Department of Pediatrics and the Helen Diller Family Cancer Center, University of California, San Francisco, San Francisco, CA; and.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM;
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.affiliation: School of Medicine and Children's Hospital, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Department of Pharmaceutical Sciences and.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D010677:Philadelphia Chromosome; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D009363:Neoplasm Proteins