Polymorphisms in genes related to oxidative stress are associated with inferior cognitive function after therapy for childhood acute lymphoblastic leukemia

Peter D. Cole, Yaron Finkelstein, Kristen E. Stevenson, Traci M. Blonquist, Veena Vijayanathan, Lewis B. Silverman, Donna S. Neuberg, Stephen E. Sallan, Philippe Robaey, Deborah P. Waber

Research output: Contribution to journalArticle

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Abstract

Purpose: Survivors of childhood acute lymphoblastic leukemia (ALL) exhibit increased rates of neurocognitive deficits. This study was conducted to test whether interpatient variability in neurocognitive outcomes can be explained by polymorphisms in candidate genes conferring susceptibility to neurocognitive decline. Methods: Neurocognitive testing was conducted in 350 pediatric leukemia survivors, treated on Dana-Farber Cancer Institute ALL Consortium Protocols 95-01 or 00-01. Genomic DNA was isolated from bone marrow collected at remission. Candidate polymorphisms were selected on the basis of prior literature, targeting genes related to drug metabolism, oxidative damage, altered neurotransmission, neuroinflammation, and folate physiology. Single nucleotide polymorphisms were detected using either a customized multiplexed Sequenom MassARRAY assay or polymerase chain reaction-based allelic discrimination assays. Multivariable logistic regression models were used to estimate the effects of genotype on neurocognitive outcomes, adjusted for the effects of demographic and treatment variables. False-discovery rate correction was made for multiple hypothesis testing, indicated as a Q value. Results: Inferior cognitive or behavioral outcomes were associated with polymorphisms in three genes related to oxidative stress and/or neuroinflammation: NOS3 (IQ, Q = 0.008; Vocabulary Q = 0.011; Matrix Reasoning Q = 0.008), SLCO2A1 (IQ Q = 0.043; Digit Span Q = 0.006; Block Design Q = 0.076), and COMT (Behavioral Assessment System for Children-2 Attention Q = 0.080; and Hyperactivity Q = 0.084). Survivors homozygous for NOS3 894T, with at least one SLCO2A1 variant G allele or with at least one GSTP1 variant allele, had lower mean estimated IQ scores than those without these genotypes. Conclusion: These data are consistent with the hypothesis that oxidative damage contributes to chemotherapy-associated neurocognitive decline among children with leukemia.

Original languageEnglish (US)
Pages (from-to)2205-2211
Number of pages7
JournalJournal of Clinical Oncology
Volume33
Issue number19
DOIs
StatePublished - Jul 1 2015

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cognition
Survivors
Oxidative Stress
Leukemia
Logistic Models
Alleles
Genotype
Genes
Gene Targeting
Vocabulary
Folic Acid
Synaptic Transmission
Single Nucleotide Polymorphism
Therapeutics
Bone Marrow
Demography
Pediatrics
Drug Therapy
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cole, P. D., Finkelstein, Y., Stevenson, K. E., Blonquist, T. M., Vijayanathan, V., Silverman, L. B., ... Waber, D. P. (2015). Polymorphisms in genes related to oxidative stress are associated with inferior cognitive function after therapy for childhood acute lymphoblastic leukemia. Journal of Clinical Oncology, 33(19), 2205-2211. https://doi.org/10.1200/JCO.2014.59.0273

Polymorphisms in genes related to oxidative stress are associated with inferior cognitive function after therapy for childhood acute lymphoblastic leukemia. / Cole, Peter D.; Finkelstein, Yaron; Stevenson, Kristen E.; Blonquist, Traci M.; Vijayanathan, Veena; Silverman, Lewis B.; Neuberg, Donna S.; Sallan, Stephen E.; Robaey, Philippe; Waber, Deborah P.

In: Journal of Clinical Oncology, Vol. 33, No. 19, 01.07.2015, p. 2205-2211.

Research output: Contribution to journalArticle

Cole, PD, Finkelstein, Y, Stevenson, KE, Blonquist, TM, Vijayanathan, V, Silverman, LB, Neuberg, DS, Sallan, SE, Robaey, P & Waber, DP 2015, 'Polymorphisms in genes related to oxidative stress are associated with inferior cognitive function after therapy for childhood acute lymphoblastic leukemia', Journal of Clinical Oncology, vol. 33, no. 19, pp. 2205-2211. https://doi.org/10.1200/JCO.2014.59.0273
Cole, Peter D. ; Finkelstein, Yaron ; Stevenson, Kristen E. ; Blonquist, Traci M. ; Vijayanathan, Veena ; Silverman, Lewis B. ; Neuberg, Donna S. ; Sallan, Stephen E. ; Robaey, Philippe ; Waber, Deborah P. / Polymorphisms in genes related to oxidative stress are associated with inferior cognitive function after therapy for childhood acute lymphoblastic leukemia. In: Journal of Clinical Oncology. 2015 ; Vol. 33, No. 19. pp. 2205-2211.
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abstract = "Purpose: Survivors of childhood acute lymphoblastic leukemia (ALL) exhibit increased rates of neurocognitive deficits. This study was conducted to test whether interpatient variability in neurocognitive outcomes can be explained by polymorphisms in candidate genes conferring susceptibility to neurocognitive decline. Methods: Neurocognitive testing was conducted in 350 pediatric leukemia survivors, treated on Dana-Farber Cancer Institute ALL Consortium Protocols 95-01 or 00-01. Genomic DNA was isolated from bone marrow collected at remission. Candidate polymorphisms were selected on the basis of prior literature, targeting genes related to drug metabolism, oxidative damage, altered neurotransmission, neuroinflammation, and folate physiology. Single nucleotide polymorphisms were detected using either a customized multiplexed Sequenom MassARRAY assay or polymerase chain reaction-based allelic discrimination assays. Multivariable logistic regression models were used to estimate the effects of genotype on neurocognitive outcomes, adjusted for the effects of demographic and treatment variables. False-discovery rate correction was made for multiple hypothesis testing, indicated as a Q value. Results: Inferior cognitive or behavioral outcomes were associated with polymorphisms in three genes related to oxidative stress and/or neuroinflammation: NOS3 (IQ, Q = 0.008; Vocabulary Q = 0.011; Matrix Reasoning Q = 0.008), SLCO2A1 (IQ Q = 0.043; Digit Span Q = 0.006; Block Design Q = 0.076), and COMT (Behavioral Assessment System for Children-2 Attention Q = 0.080; and Hyperactivity Q = 0.084). Survivors homozygous for NOS3 894T, with at least one SLCO2A1 variant G allele or with at least one GSTP1 variant allele, had lower mean estimated IQ scores than those without these genotypes. Conclusion: These data are consistent with the hypothesis that oxidative damage contributes to chemotherapy-associated neurocognitive decline among children with leukemia.",
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AU - Vijayanathan, Veena

AU - Silverman, Lewis B.

AU - Neuberg, Donna S.

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AU - Robaey, Philippe

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