Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan
Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan
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DOI：
10.1200/jco.2004.07.173
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发表时间：
2004-04-15
影响因子：
45.3
通讯作者：
Ratain, MJ
中科院分区：
文献类型：
--
作者：
Innocenti, F;Undevia, SD;Ratain, MJ
目的在接受伊立替康治疗的癌症患者中经常观察到严重的毒性。udp -葡萄糖醛酸转移酶1A1 （UGT1A1）催化活性代谢物SN-38的葡萄糖醛酸化。本研究前瞻性地评估了UGT1A1基因变异与严重毒性患病率之间的关系。患者与方法66例晚期癌症患者均接受伊立替康350mg /m(2)治疗，每3周一次。在第1周期测量毒性和药代动力学数据。UGT1A1变异（-32796 > T, -31566 > A，启动子TA indel， 211G >a, 686C >a）基因分型。结果4级中性粒细胞减少率为9.5%。4级中性粒细胞减少症在TA indel 7/7基因型患者中更为常见（6例患者中有3例，50%），而6/7（24例患者中有3例，12.5%）和6/6（29例患者中有0例，0%）更常见（P = .001）。TA indel基因型与中性粒细胞绝对计数最低点有显著相关性（7/7 < 6/7 < 6/6,P = 0.02）。与其他患者相比，7/7患者发生4级中性粒细胞减少的相对风险为9.3 （95% CI, 2.4 - 36.4）。4级中性粒细胞减少患者的预处理总胆红素水平（平均+/-标准差）（0.83 +/- 0.08 mg/dL）明显高于无4级中性粒细胞减少患者（0.47 +/- 0.03 mg/dL, P < 0.001）。-31566 > A变异似乎在TA基因型中区分了总胆红素的不同表型。-3156基因型和浓度-时间曲线下SN-38面积是In的显著预测因子（绝对中性粒细胞计数最低点，r(2) = 0.51）。结论UGT1A1基因型和总胆红素水平与严重中性粒细胞减少密切相关，可用于鉴别易患伊立替康严重毒性的肿瘤患者。假设-31566 > A变异是UGT1A1状态的更好预测因子，而不是先前报道的TA indel，这需要进一步的测试。(C) 2004年由美国临床肿瘤学会出版。
Purpose Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation.Patients and Methods Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m(2) every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (-32796 > T, -31566 > A, promoter TA indel, 211G > A, 686C > A) were genotyped.Results The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P = .001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P = .02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean +/- standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 +/- 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 +/- 0.03 mg/dL; P < .001). The -31566 > A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The -3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of In(absolute neutrophil count nadir; r(2) = 0.51).Conclusion UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the -31566 > A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing. (C) 2004 by American Society of Clinical Oncology.