title: Polymorphisms in Genes Related to Oxidative Stress Are Associated With Inferior Cognitive Function After Therapy for Childhood Acute Lymphoblastic Leukemia.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  These data are consistent with the hypothesis that oxidative damage contributes to chemotherapy-associated neurocognitive decline among children with leukemia.
authors.affiliation: Peter D. Cole, Veena Vijayanathan, Albert Einstein College of Medicine, Bronx, NY; Yaron Finkelstein, Hospital for Sick Children, University of Toronto, Toronto; Philippe Robaey, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Kristen E. Stevenson, Traci M. Blonquist, Donna S. Neuberg, Dana-Farber Cancer Institute (DFCI); Lewis B. Silverman, Stephen E. Sallan, DFCI, Boston Children's Hospital, Harvard Medical School; and Deborah P. Waber, DFCI, Harvard Medical School, Boston, MA. Peter.Cole@Einstein.YU.edu.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Cole
authors.affiliation: Peter D. Cole, Veena Vijayanathan, Albert Einstein College of Medicine, Bronx, NY; Yaron Finkelstein, Hospital for Sick Children, University of Toronto, Toronto; Philippe Robaey, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Kristen E. Stevenson, Traci M. Blonquist, Donna S. Neuberg, Dana-Farber Cancer Institute (DFCI); Lewis B. Silverman, Stephen E. Sallan, DFCI, Boston Children's Hospital, Harvard Medical School; and Deborah P. Waber, DFCI, Harvard Medical School, Boston, MA.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Finkelstein
authors.affiliation: Peter D. Cole, Veena Vijayanathan, Albert Einstein College of Medicine, Bronx, NY; Yaron Finkelstein, Hospital for Sick Children, University of Toronto, Toronto; Philippe Robaey, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Kristen E. Stevenson, Traci M. Blonquist, Donna S. Neuberg, Dana-Farber Cancer Institute (DFCI); Lewis B. Silverman, Stephen E. Sallan, DFCI, Boston Children's Hospital, Harvard Medical School; and Deborah P. Waber, DFCI, Harvard Medical School, Boston, MA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Stevenson
authors.affiliation: Peter D. Cole, Veena Vijayanathan, Albert Einstein College of Medicine, Bronx, NY; Yaron Finkelstein, Hospital for Sick Children, University of Toronto, Toronto; Philippe Robaey, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Kristen E. Stevenson, Traci M. Blonquist, Donna S. Neuberg, Dana-Farber Cancer Institute (DFCI); Lewis B. Silverman, Stephen E. Sallan, DFCI, Boston Children's Hospital, Harvard Medical School; and Deborah P. Waber, DFCI, Harvard Medical School, Boston, MA.
authors.forename: Traci M
authors.initials: TM
authors.lastname: Blonquist
authors.affiliation: Peter D. Cole, Veena Vijayanathan, Albert Einstein College of Medicine, Bronx, NY; Yaron Finkelstein, Hospital for Sick Children, University of Toronto, Toronto; Philippe Robaey, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Kristen E. Stevenson, Traci M. Blonquist, Donna S. Neuberg, Dana-Farber Cancer Institute (DFCI); Lewis B. Silverman, Stephen E. Sallan, DFCI, Boston Children's Hospital, Harvard Medical School; and Deborah P. Waber, DFCI, Harvard Medical School, Boston, MA.
authors.forename: Veena
authors.initials: V
authors.lastname: Vijayanathan
authors.affiliation: Peter D. Cole, Veena Vijayanathan, Albert Einstein College of Medicine, Bronx, NY; Yaron Finkelstein, Hospital for Sick Children, University of Toronto, Toronto; Philippe Robaey, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Kristen E. Stevenson, Traci M. Blonquist, Donna S. Neuberg, Dana-Farber Cancer Institute (DFCI); Lewis B. Silverman, Stephen E. Sallan, DFCI, Boston Children's Hospital, Harvard Medical School; and Deborah P. Waber, DFCI, Harvard Medical School, Boston, MA.
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.affiliation: Peter D. Cole, Veena Vijayanathan, Albert Einstein College of Medicine, Bronx, NY; Yaron Finkelstein, Hospital for Sick Children, University of Toronto, Toronto; Philippe Robaey, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Kristen E. Stevenson, Traci M. Blonquist, Donna S. Neuberg, Dana-Farber Cancer Institute (DFCI); Lewis B. Silverman, Stephen E. Sallan, DFCI, Boston Children's Hospital, Harvard Medical School; and Deborah P. Waber, DFCI, Harvard Medical School, Boston, MA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.affiliation: Peter D. Cole, Veena Vijayanathan, Albert Einstein College of Medicine, Bronx, NY; Yaron Finkelstein, Hospital for Sick Children, University of Toronto, Toronto; Philippe Robaey, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Kristen E. Stevenson, Traci M. Blonquist, Donna S. Neuberg, Dana-Farber Cancer Institute (DFCI); Lewis B. Silverman, Stephen E. Sallan, DFCI, Boston Children's Hospital, Harvard Medical School; and Deborah P. Waber, DFCI, Harvard Medical School, Boston, MA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.affiliation: Peter D. Cole, Veena Vijayanathan, Albert Einstein College of Medicine, Bronx, NY; Yaron Finkelstein, Hospital for Sick Children, University of Toronto, Toronto; Philippe Robaey, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Kristen E. Stevenson, Traci M. Blonquist, Donna S. Neuberg, Dana-Farber Cancer Institute (DFCI); Lewis B. Silverman, Stephen E. Sallan, DFCI, Boston Children's Hospital, Harvard Medical School; and Deborah P. Waber, DFCI, Harvard Medical School, Boston, MA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Robaey
authors.affiliation: Peter D. Cole, Veena Vijayanathan, Albert Einstein College of Medicine, Bronx, NY; Yaron Finkelstein, Hospital for Sick Children, University of Toronto, Toronto; Philippe Robaey, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Kristen E. Stevenson, Traci M. Blonquist, Donna S. Neuberg, Dana-Farber Cancer Institute (DFCI); Lewis B. Silverman, Stephen E. Sallan, DFCI, Boston Children's Hospital, Harvard Medical School; and Deborah P. Waber, DFCI, Harvard Medical School, Boston, MA.
authors.forename: Deborah P
authors.initials: DP
authors.lastname: Waber
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009483:Neuropsychological Tests; D018384:Oxidative Stress / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy*; D017741:Survivors / Q000523:psychology*