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Grant Details

Grant Number: 5R01CA108862-05 Interpret this number
Primary Investigator: Aplenc, Richard
Organization: Children'S Hosp Of Philadelphia
Project Title: Genetic Predictors of Leukemia Therapy Response
Fiscal Year: 2009
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Abstract

DESCRIPTION (provided by applicant): 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 is to test the impact of polymorphisms, involved in methotrexate (MTX) effect, on treatment outcome in the CCG-1891 sample set. The second aim is to validate associations seen in the CCG-1891 sample set in the CCG-1952 sample set. The third aim is 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 is 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.

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Publications

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.
Authors: Wray L, Vujkovic M, McWilliams T, Cannon S, Devidas M, Stork L, Aplenc R
Source: Pediatr Blood Cancer, 2014 Nov;61(11), p. 2086-8.
EPub date: 2014 Apr 16.
PMID: 24737678
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Germline genetic variation and treatment response on CCG-1891.
Authors: Sepe DM, McWilliams T, Chen J, Kershenbaum A, Zhao H, La M, Devidas M, Lange B, Rebbeck TR, Aplenc R
Source: Pediatr Blood Cancer, 2012 May;58(5), p. 695-700.
EPub date: 2011 May 25.
PMID: 21618417
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The transcobalamin (TCN2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B(12) status.
Authors: Stanis?awska-Sachadyn A, Woodside JV, Sayers CM, Yarnell JW, Young IS, Evans AE, Mitchell LE, Whitehead AS
Source: Eur J Clin Nutr, 2010 Nov;64(11), p. 1338-43.
EPub date: 2010 Sep 1.
PMID: 20808328
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The reduced folate carrier (SLC19A1) c.80G>A polymorphism is associated with red cell folate concentrations among women.
Authors: Stanis?awska-Sachadyn A, Mitchell LE, Woodside JV, Buckley PT, Kealey C, Young IS, Scott JM, Murray L, Boreham CA, McNulty H, Strain JJ, Whitehead AS
Source: Ann Hum Genet, 2009 Sep;73(Pt 5), p. 484-91.
EPub date: 2009 Jul 28.
PMID: 19650776
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Quantification of key red blood cell folates from subjects with defined MTHFR 677C>T genotypes using stable isotope dilution liquid chromatography/mass spectrometry.
Authors: Huang Y, Khartulyari S, Morales ME, Stanislawska-Sachadyn A, Von Feldt JM, Whitehead AS, Blair IA
Source: Rapid Commun Mass Spectrom, 2008 Aug;22(16), p. 2403-12.
PMID: 18634122
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Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the Children's Oncology Group.
Authors: Aplenc R, Alonzo TA, Gerbing RB, Lange BJ, Hurwitz CA, Wells RJ, Bernstein I, Buckley P, Krimmel K, Smith FO, Sievers EL, Arceci RJ, Children's Oncology Group
Source: J Clin Oncol, 2008 May 10;26(14), p. 2390-3295.
PMID: 18467731
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Influence of the cystathionine beta-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations.
Authors: Summers CM, Hammons AL, Mitchell LE, Woodside JV, Yarnell JW, Young IS, Evans A, Whitehead AS
Source: Eur J Hum Genet, 2008 Aug;16(8), p. 1010-3.
EPub date: 2008 Apr 9.
PMID: 18398434
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An insertion/deletion polymorphism of the dihydrofolate reductase (DHFR) gene is associated with serum and red blood cell folate concentrations in women.
Authors: Stanis?awska-Sachadyn A, Brown KS, Mitchell LE, Woodside JV, Young IS, Scott JM, Murray L, Boreham CA, McNulty H, Strain JJ, Whitehead AS
Source: Hum Genet, 2008 Apr;123(3), p. 289-95.
EPub date: 2008 Feb 5.
PMID: 18247058
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Pharmacogenetics of acute lymphoblastic leukemia treatment response.
Authors: Cunningham L, Aplenc R
Source: Expert Opin Pharmacother, 2007 Oct;8(15), p. 2519-31.
PMID: 17931087
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Association between the NAT1 1095C > A polymorphism and homocysteine concentration.
Authors: Stanis?awska-Sachadyn A, Jensen LE, Kealey C, Woodside JV, Young IS, Scott JM, Murray L, Boreham CA, McNulty H, Strain JJ, Whitehead AS
Source: Am J Med Genet A, 2006 Nov 1;140(21), p. 2374-7.
PMID: 17036310
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