Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients.
Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients.
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DOI：
10.1002/cncr.25735
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发表时间：
2011-07-15
期刊：
影响因子：
6.2
通讯作者：
Rennert, Gad
中科院分区：
文献类型：
--
作者：
Shulman, Katerina;Cohen, Ilana;Barnett-Griness, Ofra;Kuten, Abraham;Gruber, Stephen B.;Lejbkowicz, Flavio;Rennert, Gad
转移性结直肠癌常用伊立替康治疗，伊立替康是一种拓扑异构酶i抑制剂。UGT1A1基因编码一种代谢伊立替康的酶，其遗传变异被证明与药物毒性增加有关。我们评估了与UGT1A1*28变异相关的临床结果。纳入了329名结直肠癌患者，他们是以色列基于人群的MECC研究的参与者，接受了包括伊立替康在内的化疗方案。转移或疾病复发的病例在事件出现后的中位随访时间为2.0年。研究终点为3-4级血液学和胃肠学毒性的出现、因毒性事件（主要是中性粒细胞减少、发烧、腹泻或呕吐）而住院、住院时间和总生存期。通过片段分析从外周血DNA中分型UGT1A1*28，并报道该基因启动子TATA序列重复数。在329名参与者中，11.9%的人检测到UGT1A1*28的7/7变异。7/7携带者3-4级血液学毒性显著高于6/7和6/6携带者（分别为48.0%、10.2%、7.7%,p<0.001），毒性相关住院风险也显著高于6/7和6/6携带者（分别为45.8%、25.3%、14.4%,p=0.001）。7/7携带者治疗后2个月内的短期死亡率（分别为12.8%、5.2%和2.9%）和中位总生存期（分别为1.6年、2.0年和2.4年，log-rank p=0.01）均显著低于对照组。7/7基因型与6/6基因型的年龄阶段调整风险比（HR）为1.7（1.1-2.5）。UGT1A1*28 7/7基因型与伊立替康使用者的严重血液学毒性和较高的住院率密切相关，并预测结直肠癌患者较低的生存率。
Metastatic colorectal cancer is frequently treated with irinotecan, a topoisomerase-I inhibitor. The UGT1A1 gene encodes for an enzyme that metabolizes irinotecan and its genetic variants were shown to be associated with increased drug toxicity. We evaluated clinical outcomes associated with the UGT1A1*28 variant. Included were 329 colorectal cancer patients, participants in the Israeli population-based MECC study, treated with a chemotherapy regimen that included irinotecan. Cases with metastases or disease recurrence were followed up for a median period of 2.0 years after the appearance of the event. Study end points were appearance of grade 3–4 hematological and gastroenterological toxicity, hospitalization due to toxic events, mostly neutropenia, fever, diarrhea or vomiting, and length of hospitalization and overall survival. UGT1A1*28 was genotyped from peripheral blood DNA by fragment analysis and reported as number of TATA sequence repeats in the promoter of the gene. The 7/7 variant of UGT1A1*28 was detected in 11.9% of the 329 participants. Grade 3–4 hematological toxicity was significantly higher in 7/7 carriers compared to 6/7 and 6/6 carriers (48.0%,10.2%,7.7% correspondingly, p<0.001), and so was the risk of toxicity related hospitalization (45.8%,25.3%,14.4% correspondingly, p=0.001). Both, short-term death within 2 months of treatment onset(12.8%, 5.2% and 2.9% correspondingly) and median overall survival(1.6,2.0,2.4 years correspondingly, log-rank p=0.01) were significantly worse in the 7/7 carriers. The age-stage-adjusted hazard ratio (HR) for cases with the 7/7 genotype compared to 6/6 was 1.7 (1.1–2.5). UGT1A1*28 7/7 genotype is strongly associated with severe hematologic toxicity and higher hospitalization rate and predicts lower survival of colorectal cancer in users of Irinotecan.
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