Ashton Lesley J, Murray Jayne E, Haber Michelle, Marshall Glenn M, Ashley David M, Norris Murray D
Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia.
Pharmacogenet Genomics. 2007 Sep;17(9):709-17. doi: 10.1097/FPC.0b013e3280e1cc92.
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.
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.
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 NAT111 allele variant were significantly less likely to relapse or die compared with those with NAT110 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).
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.
虽然多项研究表明药物代谢酶基因多态性可能会影响儿童白血病的治疗效果，但尚未对神经母细胞瘤患儿进行全面研究。本研究的目的是在209例神经母细胞瘤患儿队列中，鉴定与复发或死亡风险相关的Ⅰ期和Ⅱ期药物代谢酶编码基因的多态性。
采用实时荧光定量PCR等位基因鉴别技术对神经母细胞瘤患儿DNA中的多态性进行特征分析。检测了三大类基因：细胞色素P450、谷胱甘肽-S-转移酶和N-乙酰转移酶。采用Kaplan-Meier法计算累积无事件生存率。使用Cox比例风险模型检验所选因素对无事件生存率的影响。
如先前报道，MYCN扩增（风险比=4.25，95%置信区间=2.76-6.56，P<0.001）、不良分期（风险比=4.14，95%置信区间=2.3-7.47，P<0.001）或诊断时年龄大于1岁（风险比=1.86，95%置信区间=1.19-2.92，P=0.007）均与复发或死亡风险增加相关。与携带NAT110或其他NAT1等位基因变体的患儿相比，携带NAT111等位基因变体的患儿复发或死亡的可能性显著降低（P<0.0..1）。在多变量分析中，校正MYCN扩增、分期和诊断时年龄后，GSTM1基因缺失的患儿在随访期间复发或死亡的可能性更大（风险比=1.6，95%置信区间=1.02-2.9，P=0.04）。
这些观察结果表明，NAT1*11变体和GSTM1野生型基因型有助于神经母细胞瘤患儿获得更有利的预后，并且首次证明了儿童神经母细胞瘤中NAT1和GSTM1基因型之间的关系。
