Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia
Year: 2015
Type: article
Study design: Observational Study
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.
Source: Blood
Authors: Seth E. Karol, Leonard A. Mattano, Wenjian Yang, Kelly W. Maloney, Colton Smith, ChengCheng Liu, Laura B. Ramsey, Christian A. Fernandez, Tamara Y. Chang, Geoffrey Neale, Cheng Cheng, Elaine Mardis, Robert Fulton, Paul Scheet, F. Anthony San Lucas, Eric C. Larsen, Mignon L. Loh, Elizabeth A. Raetz, Stephen P. Hunger, Meenakshi Devidas, Mary V. Relling
Institutions: St. Jude Children's Research Hospital, Children's Hospital Colorado, Washington University in St. Louis, The University of Texas MD Anderson Cancer Center, Maine Medical Center, Maine Medical Center, University of California, San Francisco, University of California San Francisco Medical Center, University of Utah, Children's Hospital of Philadelphia, University of Pennsylvania, University of Florida Health, University of Florida
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G111615301, G1399567684, G1860110607, G2117365975, G22842288, G2484864540, G2554726104, G2634635869, G2688579988, G2901481919, Glucocorticoids in Lymphoblastic Leukemia, Pharmacogenomics of Childhood Leukemia ALL, Support for Human Specimen Banking in NCI-Sponsored Clinical Trials-(CGB), G3942302684, G421865639, Children's Oncology Group Statistics and Data Center, G46020690, G5150888020, G609259107, G6626909389, PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL), G860380395, G8649056308, Cancer Center Support Grant, Cancer Center Support Grant (CCSG), G997771125
OpenAlex ID: W2321687835