title: Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia.
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.
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Seth E
authors.initials: SE
authors.lastname: Karol
authors.affiliation: HARP Pharma Consulting, Mystic, CT;
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Mattano
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.affiliation: Center for Cancer and Blood Disorders, Children's Hospital Colorado, Denver, CO;
authors.forename: Kelly W
authors.initials: KW
authors.lastname: Maloney
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Colton
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: ChengCheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ramsey
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Christian A
authors.initials: CA
authors.lastname: Fernandez
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Tamara Y
authors.initials: TY
authors.lastname: Chang
authors.affiliation: Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO;
authors.forename: Elaine
authors.initials: E
authors.lastname: Mardis
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO;
authors.forename: Robert
authors.initials: R
authors.lastname: Fulton
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Paul
authors.initials: P
authors.lastname: Scheet
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: F Anthony
authors.initials: FA
authors.lastname: San Lucas
authors.affiliation: Department of Pediatrics, Maine Medical Center, Portland, ME;
authors.forename: Eric C
authors.initials: EC
authors.lastname: Larsen
authors.affiliation: Department of Pediatrics, University of California School of Medicine, San Francisco, CA;
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT;
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Raetz
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; and.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D055419:Bone Morphogenetic Protein 7 / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008297:Male; D010020:Osteonecrosis / Q000453:epidemiology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications* / Q000628:therapy*; D012307:Risk Factors
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7