RESUMO
OBJECTIVE: Neuropsychological problems occurrence varies among childhood cancer survivors, and associated risk factors have not been fully deciphered. We wanted to study the role of genetic variants in behavioral problems in this population. STUDY DESIGN: Behavioral problems in pediatric acute lymphoblastic leukemia patients (n=138) were investigated longitudinally, using the Child Behavior Checklist questionnaire and multilevel statistical modeling. Thirty-four candidate polymorphisms, related to anticancer drug effects, were investigated. RESULTS: NOS3 gene functional polymorphisms showed significant association: patients homozygous for the minor allele at investigated loci showed decreased externalizing behavioral problems scores over time (t tests: T-786C n=69, P=0.003; G894T n=71, P=0.065). The effect was even more pronounced for individuals that are homozygous for the -786C844T haplotype (t test, n=69, P<0.001) and results were supported by multilevel modeling analyses (P<0.001). No such association was observed for internalizing behavioral problems. CONCLUSION: NOS3 variants modulate externalizing problems individual trajectories, likely in relationship with glucocorticoid exposure.
Assuntos
Transtornos do Comportamento Infantil/etiologia , DNA de Neoplasias/genética , Óxido Nítrico Sintase Tipo III/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/psicologia , Adolescente , Criança , Transtornos do Comportamento Infantil/induzido quimicamente , Transtornos do Comportamento Infantil/enzimologia , Transtornos do Comportamento Infantil/genética , Pré-Escolar , Seguimentos , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Haplótipos , Homozigoto , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inquéritos e Questionários , Sobreviventes/psicologiaRESUMO
Childhood acute lymphoblastic leukemia patients (n=310) were analyzed for four SNPs in the NR3C1 gene. Polymorphisms -627A/G, intron 2 +646C/G and 9bT/C were all associated with reduced event-free survival. Haplotypes composed of AGT alleles at these loci and tagged by the intron 2 +646G variant also associated with lower event-free survival (p=0.03). The progressive impact of this haplotype on outcome was seen with two copies associated with reduced overall survival (p=0.05). Quantitative mRNA analysis in lymphoblastoid cell lines showed that carriers of the AGT haplotype had a higher ratio of GR gamma/alpha isoforms (p=0.04), which possibly explains its association with reduced event-free survival and overall survival.
