Polymorphisms in genes encoding drug metabolizing enzymes and their influence on the outcome of children with neuroblastoma.
BACKGROUND
Although several studies have shown that drug metabolizing enzyme gene polymorphisms may influence the impact of therapy in childhood leukemia, no comprehensive investigations have been carried out in children with neuroblastoma. The aim of this study was to identify polymorphisms in the genes encoding phase I and II drug metabolizing enzymes associated with the risk of relapse or death in a cohort of 209 children with neuroblastoma.


METHODS
Real-time PCR allelic discrimination was used to characterize the presence of polymorphisms in DNA from children with neuroblastoma. Three broad gene categories were examined: cytochrome P450, glutathione-S-transferase and N-acetyltransferase. Cumulative event-free survival was computed by the Kaplan-Meier method. The influence of selected factors on event-free survival was tested using the Cox proportional hazards model.


RESULTS
As previously reported, amplification of MYCN (hazards ratio=4.25, 95% confidence interval=2.76-6.56, P<0.001), unfavorable stage (hazard ratio=4.14, 95% confidence interval=2.3-7.47, P<0.001) or age more than 1 year at diagnosis (hazard ratio=1.86, 95% confidence interval=1.19-2.92, P=0.007) were all associated with an increased risk of relapse or death. Carriers of a NAT1*11 allele variant were significantly less likely to relapse or die compared with those with NAT1*10 or other NAT1 allele variants (P<0.001). In multivariate analysis, children who were GSTM1 null were more likely to relapse or die during follow-up after adjusting for MYCN amplification, stage and age at diagnosis (hazard ratio=1.6, 95% confidence interval=1.02-2.9, P=0.04).


CONCLUSIONS
These observations suggest that the NAT1*11 variant and the GSTM1 wild-type genotype contribute to a more favorable outcome in patients treated for neuroblastoma and are the first to demonstrate a relationship between NAT1 and GSTM1 genotypes in childhood neuroblastoma.
Ashton
Lesley J
LJ
Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia. lashton@ccia.unsw.edu.au
Murray
Jayne E
JE
Haber
Michelle
M
Marshall
Glenn M
GM
Ashley
David M
DM
Norris
Murray D
MD
D000293:Adolescent; D000483:Alleles; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011379:Prognosis
D001191:Arylamine N-Acetyltransferase; D003577:Cytochrome P-450 Enzyme System; D017931:DNA Primers; D005982:Glutathione Transferase; D007527:Isoenzymes; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D004364:Pharmaceutical Preparations; C459801:MYCN protein, human; C089384:N-acetyltransferase 1