Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia

Karol, Seth E.; Yang, Wenjian; Driest, Sara L. Van; Chang, Tamara; Kaste, Sue C.; Bowton, Erica; Basford, Melissa A.; Bastarache, Lisa; Roden, Dan M.; Denny, Joshua C.; Larsen, Eric; Winick, Naomi J.; Carroll, William L.; Cheng, Cheng; Pei, Deqing; Fernandez, Christian A.; Liu, Chengcheng; Smith, Colton; Loh, Mignon L.; Raetz, Elizabeth A.; Hunger, Stephen P.; Scheet, Paul; Jeha, Sima; Pui, Ching Hon; Evans, William E.; Devidas, Meenakshi; Mattano, Leonard A.; Relling, Mary V.

doi:10.1182/blood-2015-05-643601

Cited by 102 publications

(114 citation statements)

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“…6,9,[65][66][67][68] Polymorphisms in the plasminogen activator inhibitor-1 (PAI-1) gene were initially reported to be associated with an increased risk of osteonecrosis, 4,66 but this finding could not be confirmed by subsequent GWAS studies. 68 Osteonecrosis in children with ALL haematologica | 2016; 101(11) Likewise, findings about polymorphisms involved in lipid homeostasis (acid phosphatase locus 1, ACP1), 6 antifolate pharmacodynamics (thymidylate synthetase, TYMS), and steroid hormone response (vitamin D receptor, VDR), have been reported to be associated with osteonecrosis, 9 but were not reproducible in GWAS studies. 68 According to recent GWAS studies, the glutamate receptor pathway seems to be of crucial importance for the pathogenesis of osteonecrosis in patients with prolonged exposure to corticosteroids.…”

Section: Genetic Risk Factorsmentioning

confidence: 77%

“…Mechanical load opens mechanosensitive calcium channels in osteocytes, leading to exocytosis of glutamate, which activates osteoblast receptors and impairs endothelial barrier function. [67][68][69][70] In addition, SNPs in adipogenesis pathways and in enhancers active in mesenchymal stem cells are significantly associated with osteonecrosis development. 67 Bone morphogenetic protein (BMP) is toxic to vascular smooth muscle and is released in response to bone damage and mechanical stress.…”

Section: Genetic Risk Factorsmentioning

confidence: 99%

“…68 Osteonecrosis in children with ALL haematologica | 2016; 101(11) Likewise, findings about polymorphisms involved in lipid homeostasis (acid phosphatase locus 1, ACP1), 6 antifolate pharmacodynamics (thymidylate synthetase, TYMS), and steroid hormone response (vitamin D receptor, VDR), have been reported to be associated with osteonecrosis, 9 but were not reproducible in GWAS studies. 68 According to recent GWAS studies, the glutamate receptor pathway seems to be of crucial importance for the pathogenesis of osteonecrosis in patients with prolonged exposure to corticosteroids. Mechanical load opens mechanosensitive calcium channels in osteocytes, leading to exocytosis of glutamate, which activates osteoblast receptors and impairs endothelial barrier function.…”

Section: Genetic Risk Factorsmentioning

confidence: 99%

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Osteonecrosis in children with acute lymphoblastic leukemia

et al. 2016

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Section: Genetic Risk Factorsmentioning

confidence: 77%

Section: Genetic Risk Factorsmentioning

confidence: 99%

Section: Genetic Risk Factorsmentioning

confidence: 99%

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Osteonecrosis in children with acute lymphoblastic leukemia

et al. 2016

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“…[9][10][11] However, age remains the strongest and most consistently identified factor, with patients 10 to 20 years old at greatest risk. 10,11,[13][14][15] Given this age-related risk, the majority of children in prior investigations of genetic predisposition to osteonecrosis were .10 years. 10,15 However, because ALL is so common in young children, up to 40% of osteonecrosis cases develop in children ,10 years of age.…”

Section: Introductionmentioning

confidence: 99%

“…10,11,[13][14][15] Given this age-related risk, the majority of children in prior investigations of genetic predisposition to osteonecrosis were .10 years. 10,15 However, because ALL is so common in young children, up to 40% of osteonecrosis cases develop in children ,10 years of age. 10 In this study, we identified genetic factors associated with the development of osteonecrosis in the largest cohort of SR ALL patients evaluated to date and validated these findings in a cohort of NCI highrisk ALL patients ,10 years of age.…”

Section: Introductionmentioning

confidence: 99%

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

Karol

Mattano

Yang

et al. 2016

Blood

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• Variants in genes important for mesenchymal stem cell differentiation influence the risk of osteonecrosis in children with ALL under 10 years old.• Variants in genes in the glutamate signaling pathway influence osteonecrosis in children with ALL regardless of age.Osteonecrosis is a dose-limiting toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL [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 3 10 28. 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. (Blood. 2016;127(5):558-564)

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Association of Inherited Genetic Factors With Drug-Induced Hepatic Damage Among Children With Acute Lymphoblastic Leukemia

et al. 2022

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ImportanceAcute lymphoblastic leukemia (ALL) is the most common childhood cancer. Hepatotoxic effects, including hyperbilirubinemia and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, are common during all phases of therapy and are linked to several chemotherapeutic agents, including asparaginase, mercaptopurine, and methotrexate.ObjectiveTo determine which genetic variants were associated with hyperbilirubinemia and elevated ALT and AST levels in children, adolescents, and young adults treated for ALL.Design, Setting, and ParticipantsThis retrospective analysis of a multiethnic genome-wide association study was conducted between January 1, 2019, and April 15, 2022, including patients treated as part of Children’s Oncology Group (COG) trials with centers in the United States, Canada, and Australia, which accrued data from December 29, 2003, to January 21, 2011 (AALL0232), and from January 22, 2007, to July 24, 2014 (AALL0434). Germline genotypes were interrogated using genome-wide arrays and imputed using a National Institutes of Health TOPMed Imputation server. Mixed-effects logistic regressions were used to account for multiple episodes for an individual patient. Genotype × treatment phase interaction was tested to uncover phase-specific genetic risk factors.ExposuresTotal duration of multiagent protocol chemotherapy ranging from 2.5 to 3.5 years.Main Outcomes and MeasuresThe primary outcomes were National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) hyperbilirubinemia of grade 3 or higher and elevated liver ALT and AST levels.ResultsA total of 3557 participants were included in the analysis (2179 [61.3%] male; median age, 11.1 [range, 1-30] years). Among 576 known variants associated with these liver function test results in the general population, UGT1A1 variant rs887829 and PNPLA3 variant rs738409 were associated with increased risk of hyperbilirubinemia (odds ratio [OR], 2.18 [95% CI, 1.89-2.53]; P = 6.7 × 10−27) and ALT and AST levels (OR, 1.27 [95% CI, 1.15-1.40]; P = 3.7 × 10−7), respectively, during treatment for ALL. Corresponding polygenic risk scores were associated with hepatotoxic effects across all therapy phases and were largely driven by UGT1A1 and PNPLA3 variants. Genome-wide association analysis revealed an age-specific variant near the CPT1A gene that was only associated with elevated ALT and AST levels among patients younger than 10 years (OR, 1.28 [95% CI, 1.18-1.39]; P = 8.7 × 10−10).Conclusions and RelevanceThese results suggest a strong genetic basis for interpatient variability in hyperbilirubinemia and aminotransferase level elevations during leukemia chemotherapy.

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Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia

Abstract: Key Points Comprehensive study of glucocorticoid-induced osteonecrosis identifies glutamate receptor gene variants as risk factors.

Cited by 102 publications

References 48 publications

Osteonecrosis in children with acute lymphoblastic leukemia

Osteonecrosis in children with acute lymphoblastic leukemia

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

Association of Inherited Genetic Factors With Drug-Induced Hepatic Damage Among Children With Acute Lymphoblastic Leukemia

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