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Blood. 2015 Jul 2;126(1):69-75. doi: 10.1182/blood-2015-02-628800. Epub 2015 May 18.

Genome-wide analysis links NFATC2 with asparaginase hypersensitivity.

Author information

1
Department of Pharmaceutical Sciences, and.
2
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN;
3
Maine Children's Cancer Program, Scarborough, ME;
4
Department of Hematology and Oncology, Cook Children's Medical Center, Fort Worth, TX;
5
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
6
Department of Pediatrics, University of California School of Medicine, San Francisco, CA;
7
Department of Pediatrics, University of Utah, Salt Lake City, UT;
8
University of Texas Southwestern Medical Center, Dallas, TX;
9
Division of Pediatric Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA;
10
Department of Pediatrics, New York University Medical Center, New York, NY; and.
11
Department of Biostatistics, Colleges of Medicine, Public Health & Health Professions, University of Florida, Gainesville, FL.

Abstract

Asparaginase is used to treat acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions can lead to suboptimal asparaginase exposure. Our objective was to use a genome-wide approach to identify loci associated with asparaginase hypersensitivity in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols Total XIIIA (n = 154), Total XV (n = 498), and Total XVI (n = 271), or Children's Oncology Group protocols POG 9906 (n = 222) and AALL0232 (n = 2163). Germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the Illumina Exome BeadChip array. In multivariate logistic regression, the intronic rs6021191 variant in nuclear factor of activated T cells 2 (NFATC2) had the strongest association with hypersensitivity (P = 4.1 × 10(-8); odds ratio [OR] = 3.11). RNA-seq data available from 65 SJCRH ALL tumor samples and 52 Yoruba HapMap samples showed that samples carrying the rs6021191 variant had higher NFATC2 expression compared with noncarriers (P = 1.1 × 10(-3) and 0.03, respectively). The top ranked nonsynonymous polymorphism was rs17885382 in HLA-DRB1 (P = 3.2 × 10(-6); OR = 1.63), which is in near complete linkage disequilibrium with the HLA-DRB1*07:01 allele we previously observed in a candidate gene study. The strongest risk factors for asparaginase allergy are variants within genes regulating the immune response.

PMID:
25987655
PMCID:
PMC4492197
DOI:
10.1182/blood-2015-02-628800
[Indexed for MEDLINE]
Free PMC Article

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