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Blood. 2015 Jan 22;125(4):680-6. doi: 10.1182/blood-2014-09-595744. Epub 2014 Dec 2.

A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults.

Author information

1
Department of Pharmaceutical Sciences and.
2
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN;
3
Department of Pharmaceutical Sciences and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China;
4
University of New Mexico Cancer Center, Albuquerque, NM;
5
Department of Biostatistics, Colleges of Medicine, Public Health & Health Professions, University of Florida, Gainesville, FL;
6
Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM;
7
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY;
8
Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH;
9
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL;
10
Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT;
11
The Ohio State University, Nationwide Children's Hospital, Columbus, OH;
12
Comprehensive Cancer Center, The Ohio State University, Columbus, OH;
13
Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Alliance of Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester;
14
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL;
15
Section of Molecular Hematology & Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
16
The University of Texas MD Anderson Cancer Center, Houston, TX;
17
Department of Medicine (Oncology), Albert Einstein College of Medicine, Yeshiva University, New York, NY;
18
Rambam Medical Center, Haifa, Israel;
19
Hematologic Malignancies Program, Hematology-Oncology Division, University of Pennsylvania, Philadelphia, PA;
20
Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;
21
Laboratory of Experimental Immunology, National Cancer Institute, Frederick, MD;
22
Department of Bioengineering & Therapeutic Science and Department of Medicine, University of California, San Francisco, San Francisco, CA;
23
Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA;
24
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
25
Office of Cancer Genomics, National Cancer Institute, Bethesda, MD;
26
Department of Pediatrics and the Helen Diller Family Cancer Center, University of California, San Francisco, San Francisco, CA; and.
27
School of Medicine and Children's Hospital, University of Colorado School of Medicine, Aurora, CO.

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.

PMID:
25468567
PMCID:
PMC4304112
DOI:
10.1182/blood-2014-09-595744
[Indexed for MEDLINE]
Free PMC Article

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