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Blood. 2016 Feb 4;127(5):558-64. doi: 10.1182/blood-2015-10-673848. Epub 2015 Nov 20.

Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia.

Author information

1
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
2
HARP Pharma Consulting, Mystic, CT;
3
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
4
Center for Cancer and Blood Disorders, Children's Hospital Colorado, Denver, CO;
5
Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN;
6
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN;
7
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO;
8
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX;
9
Department of Pediatrics, Maine Medical Center, Portland, ME;
10
Department of Pediatrics, University of California School of Medicine, San Francisco, CA;
11
Department of Pediatrics, University of Utah, Salt Lake City, UT;
12
Department of Pediatrics, Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; and.
13
Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL.

Abstract

Osteonecrosis is a dose-limiting toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL). Prior studies on the genetics of osteonecrosis have focused on patients ≥10 years of age, leaving the genetic risk factors for the larger group of children <10 years incompletely understood. Here, we perform the first evaluation of genetic risk factors for osteonecrosis in children <10 years. The discovery cohort comprised 82 cases of osteonecrosis and 287 controls treated on Children's Oncology Group (COG) standard-risk ALL protocol AALL0331 (NCT00103285, https://clinicaltrials.gov/ct2/show/NCT00103285), with results tested for replication in 817 children <10 years treated on COG protocol AALL0232 (NCT00075725, https://clinicaltrials.gov/ct2/show/NCT00075725). The top replicated single nucleotide polymorphisms (SNPs) were near bone morphogenic protein 7 [BMP7: rs75161997, P = 5.34 × 10(-8) (odds ratio [OR] 15.0) and P = .0498 (OR 8.44) in the discovery and replication cohorts, respectively] and PROX1-antisense RNA1 (PROX1-AS1: rs1891059, P = 2.28 × 10(-7) [OR 6.48] and P = .0077 [OR 3.78] for the discovery and replication cohorts, respectively). The top replicated nonsynonymous SNP, rs34144324, was in a glutamate receptor gene (GRID2, P = 8.65 × 10(-6) [OR 3.46] and P = .0136 [OR 10.8] in the discovery and replication cohorts, respectively). In a meta-analysis, the BMP7 and PROX1-AS1 variants (rs75161997 and rs1891059, respectively) met the significance threshold of <5 × 10(-8). Top replicated SNPs were enriched in enhancers active in mesenchymal stem cells, and analysis of annotated genes demonstrated enrichment in glutamate receptor and adipogenesis pathways. These data may provide new insights into the pathophysiology of osteonecrosis.

PMID:
26590194
PMCID:
PMC4742546
DOI:
10.1182/blood-2015-10-673848
[Indexed for MEDLINE]
Free PMC Article

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