Although acute myeloid leukemia (AML) causes substantial treatment burden in both children and adults, AML treatment response remains incompletely understood. This application proposes a genome-wide association study (GWAS) of pediatric AML treatment response. Two hypotheses underlie this application. First, somatic genetic variation will modify AML relapse and treatment related infection risk. Second, clinical trial simulations (CTS) may define how genetic variation data may be used to modify AML treatment. These hypotheses will be tested in three specific aims.
Aim 1 will use the Illumina Human 610 HH Bead Chip to perform a GWAS with 840 patients to identify genotypes associated with AML relapse and infectious complication risk.
Aim 2 will use the Illumina Infinium"""""""" Chip to validate 4% of SNPs found in Aim 1 in 1,160 Caucasian patients and 750 non-Caucasian patients.
Aim 3 will use CTS to test the clinical applicability of infection susceptibility genotypes discovered and validated in the first two aims. This application has significance both as the first GWAS in AML and as a novel step towards translating genetic variability data into the clinical care of patients. Furthermore, since pediatric and adult AML share common molecular pathologies and treatment strategies, this research may inform the care of both adult and pediatric AML patients.

Public Health Relevance

Acute myeloid leukemia (AML) causes a substantial disease and treatment burden in both children and adults. This application will provide data on the role of somatic genetic variability in AML treatment response and will use clinical trial simulations to model the application of genotype data to clinical patient care. Thus, this application may not only inform the care of adult and pediatric AML patients, but may also provide important insights into the translation of genotype data into patient care.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Epidemiology of Cancer Study Section (EPIC)
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Simonds, Naoko
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Children's Hospital of Philadelphia
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Vujkovic, Marijana; Attiyeh, Edward F; Ries, Rhonda E et al. (2015) Concordance of copy number alterations using a common analytic pipeline for genome-wide analysis of Illumina and Affymetrix genotyping data: a report from the Children's Oncology Group. Cancer Genet 208:408-13
Seif, Alix E; Walker, Dana M; Li, Yimei et al. (2015) Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric oncology patients. Pediatr Blood Cancer 62:704-9
Vujkovic, Marijana; Kershenbaum, Aaron; Wray, Lisa et al. (2015) Associations between genetic variants in folate and drug metabolizing pathways and relapse risk in pediatric acute lymphoid leukemia on CCG-1952. Leuk Res Rep 4:47-50
Fisher, Brian T; Sammons, Julia Shaklee; Li, Yimei et al. (2014) Variation in Risk of Hospital-Onset Clostridium difficile Infection Across β-Lactam Antibiotics in Children With New-Onset Acute Lymphoblastic Leukemia. J Pediatric Infect Dis Soc 3:329-35
Fisher, Brian T; Harris, Tracey; Torp, Kari et al. (2014) Establishment of an 11-year cohort of 8733 pediatric patients hospitalized at United States free-standing children's hospitals with de novo acute lymphoblastic leukemia from health care administrative data. Med Care 52:e1-6
Fisher, Brian T; Kavcic, Marko; Li, Yimei et al. (2014) Antifungal prophylaxis associated with decreased induction mortality rates and resources utilized in children with new-onset acute myeloid leukemia. Clin Infect Dis 58:502-8
Lee, Grace E; Sung, Lillian; Fisher, Brian T et al. (2014) Gene expression profiling to predict viridans group streptococcal and invasive fungal infection in pediatric acute myeloid leukemia: a brief report from the Children's Oncology Group. Acta Haematol 131:167-9
Fisher, Brian T; Singh, Sonia; Huang, Yuan-Shung et al. (2014) Induction mortality, ATRA administration, and resource utilization in a nationally representative cohort of children with acute promyelocytic leukemia in the United States from 1999 to 2009. Pediatr Blood Cancer 61:68-73
Seif, Alix E; Fisher, Brian T; Li, Yimei et al. (2014) Patient and hospital factors associated with induction mortality in acute lymphoblastic leukemia. Pediatr Blood Cancer 61:846-52
Wray, Lisa; Vujkovic, Marijana; McWilliams, Thomas et al. (2014) TPMT and MTHFR genotype is not associated with altered risk of thioguanine-related sinusoidal obstruction syndrome in pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 61:2086-8

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