Abstract

Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Although many children are cured by risk stratified therapy, a significant portion either relapse or experience therapy related toxicity. We hypothesize that ALL treatment response is a complex trait which may be partially explained by common genotypic variants. This project will evaluate the association between genotypic variants and therapy outcome on two national randomized clinical trials (CCG-1891 and CCG-1952) of standard risk ALL. This study has four aims.
The first aim i s to test the impact of polymorphisms, involved in methotrexate (MTX) effect, on treatment outcome in the CCG-1891 sample set.
The second aim i s to validate associations seen in the CCG-1891 sample set in the CCG-1952 sample set.
The third aim i s to extend and apply new methods for the analysis of gene-gene interactions to a combined sample set of CCG-1891 and CCG-1952.
The fourth aim i s to develop a predictive model of ALL relapse risk that includes genotype data. Our prior work has demonstrated in the CCG-1891 sample set that patients homozygous for the MTHFR C677T variant have an increased rate of relapse. We hypothesize that other polymorphisms in the genes mediating MTX effect will modify relapse and toxicity risk. Second, we hypothesize that significant associations seen in CCG-1891 will replicate in CCG-1952. Third, we hypothesize that patterning with recursive partitioning (PRP) will allow identification of polymorphism groups that predict relapse and toxicity. Fourth, we hypothesize that genotype data will improve the clinical utility of predictive models of relapse risk. We propose to test these hypotheses with a nested case control study of 120 relapse patients and 360 patients in continuous remission (CR) on CCG-1891, and of 200 relapse patients and 600 patients in CR on CCG-1952. This application will identify and validate polymorphisms that modify ALL therapy outcome and will rigorously evaluate the additional predictive information captured in genotype data.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108862-05
Application #
7616583
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Sansbury, Leah B
Project Start
2005-06-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2009
Total Cost
$256,197
Indirect Cost

  Institution

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

  Publications

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
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
Sepe, Dana M; McWilliams, Thomas; Chen, Jinbo et al. (2012) Germline genetic variation and treatment response on CCG-1891. Pediatr Blood Cancer 58:695-700
Stanislawska-Sachadyn, A; Woodside, J V; Sayers, C M et al. (2010) The transcobalamin (TCN2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B(12) status. Eur J Clin Nutr 64:1338-43
Stanis?awska-Sachadyn, Anna; Mitchell, Laura E; Woodside, Jayne V et al. (2009) The reduced folate carrier (SLC19A1) c.80G>A polymorphism is associated with red cell folate concentrations among women. Ann Hum Genet 73:484-91
Summers, Carolyn M; Hammons, Andrea L; Mitchell, Laura E et al. (2008) Influence of the cystathionine beta-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations. Eur J Hum Genet 16:1010-3
Huang, Yuehua; Khartulyari, Stefanie; Morales, Megan E et al. (2008) Quantification of key red blood cell folates from subjects with defined MTHFR 677C>T genotypes using stable isotope dilution liquid chromatography/mass spectrometry. Rapid Commun Mass Spectrom 22:2403-12
Aplenc, Richard; Alonzo, Todd A; Gerbing, Robert B et al. (2008) Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the Children's Oncology Group. J Clin Oncol 26:2390-3295
Stanislawska-Sachadyn, Anna; Brown, Karen S; Mitchell, Laura E et al. (2008) An insertion/deletion polymorphism of the dihydrofolate reductase (DHFR) gene is associated with serum and red blood cell folate concentrations in women. Hum Genet 123:289-95
Cunningham, Lea; Aplenc, Richard (2007) Pharmacogenetics of acute lymphoblastic leukemia treatment response. Expert Opin Pharmacother 8:2519-31

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