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Polymorphisms in genes encoding drug metabolizing enzymes and their influence on the outcome of children with neuroblastoma.

Abstract：

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.

journal_name

Pharmacogenet Genomics

journal_title

Pharmacogenetics and genomics

authors

Ashton LJ,Murray JE,Haber M,Marshall GM,Ashley DM,Norris MD

doi

10.1097/FPC.0b013e3280e1cc92

subject

Has Abstract

pub_date

2007-09-01 00:00:00

pages

709-17

issue

eissn

1744-6872

issn

1744-6880

pii

01213011-200709000-00004

journal_volume

pub_type

杂志文章

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Polymorphisms in genes encoding drug metabolizing enzymes and their influence on the outcome of children with neuroblastoma.