Polymorphisms in Genes Related to Oxidative Stress Are Associated With Inferior Cognitive Function After Therapy for Childhood XXXX .

@entity1501 @entity1 @entity5549 @entity981 @entity9554 @entity45602 @entity5 @entity149 @entity1778 @entity4191 @entity4334
PURPOSE: Survivors of childhood @entity981 ( @entity981 ) exhibit increased rates of @entity149 . This study was conducted to test whether interpatient variability in neurocognitive outcomes can be explained by polymorphisms in candidate genes conferring susceptibility to @entity149 . METHODS: Neurocognitive testing was conducted in 350 pediatric @entity1778 survivors, treated on Dana-Farber @entity5 Institute @entity981 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 @entity1501 physiology. Single @entity4334 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: @entity9554 (IQ, Q = 0.008; Vocabulary Q = 0.011; Matrix Reasoning Q = 0.008), @entity45602 (IQ Q = 0.043; Digit Span Q = 0.006; Block Design Q = 0.076), and @entity5549 (Behavioral Assessment System for @entity1 -2 Attention Q = 0.080; and Hyperactivity Q = 0.084). Survivors homozygous for @entity9554 894T, with at least one @entity45602 variant G allele or with at least one @entity4191 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 @entity149 among @entity1 with @entity1778 .
