Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA133881-02
Application #
8042588
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Simonds, Naoko
Project Start
2010-03-09
Project End
2014-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
2
Fiscal Year
2011
Total Cost
$572,691
Indirect Cost

  Institution

Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Getz, Kelly D; He, Christy; Li, Yimei et al. (2018) Successful merging of data from the United Network for Organ Sharing and the Pediatric Health Information System databases. Pediatr Transplant 22:e13168
Citrin, Rebecca; Getz, Kelly D; Li, Yimei et al. (2018) The epidemiology of rasburicase use in paediatric patients with acute lymphoblastic leukaemia and non-Hodgkin lymphoma. Br J Haematol :
Vujkovic, Marijana; Attiyeh, Edward F; Ries, Rhonda E et al. (2017) Genomic architecture and treatment outcome in pediatric acute myeloid leukemia: a Children's Oncology Group report. Blood 129:3051-3058
Lamba, Jatinder K; Chauhan, Lata; Shin, Miyoung et al. (2017) CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children's Oncology Group Trial AAML0531. J Clin Oncol 35:2674-2682
Winestone, Lena E; Getz, Kelly D; Miller, Tamara P et al. (2017) The role of acuity of illness at presentation in early mortality in black children with acute myeloid leukemia. Am J Hematol 92:141-148
Vujkovic, Marijana; Aplenc, Richard; Alonzo, Todd A et al. (2016) Comparing Analytic Methods for Longitudinal GWAS and a Case-Study Evaluating Chemotherapy Course Length in Pediatric AML. A Report from the Children's Oncology Group. Front Genet 7:139
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
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
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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