[Relationship between UGT1A1 gene polymorphisms and irinotecan-induced severe adverse events].

Objective: To investigate the relationship between UGT1A1*6, UGT1A1*28, UGT1A1*60 and UGT1A1*93 polymorphisms and irinotecan-induced severe adverse reactions(grade 3-4 delayed diarrhea and neutropenia) in Chinese cancer patients. Methods: A total of 141 cancer patients treated with irinotecan were enrolled in this study. Peripheral venous blood was collected and genomic DNA was extracted. The genetic polymorphisms of UGT1A1*6, UGT1A1*28, UGT1A1*60 and UGT1A1*93 were analyzed by PCR and direct sequencing. The adverse reactions during chemotherapy were observed and recorded. The incidence of severe adverse reactions was compared among patients with different genotypes. Results: Among 141 patients, the cases with UGT1A1*6 GG, GA and AA genotypes were 71, 54 and 16, while those with UGT1A1*28 TA6/6, TA6/7 and TA7/7 genotypes were 105, 33 and 3, respectively. The cases with UGT1A1*60 AA, AC and CC genotypes were 52, 80 and 9, while those with UGT1A1*93 GG, GA and AA genotypes were 105, 32 and 4, respectively. The patients with grade 3-4 delayed diarrhea and neutropenia were 23 and 56, respectively. Multivariate logistic regression analysis showed that UGT1A1*6 and UGT1A1*60 genetic polymorphisms were independent factors influencing the occurrence of grade 3-4 delayed diarrhea. The risk of grade 3-4 delayed diarrhea in homozygous AA carriers of UGT1A1*6 increased 3.79 times compared with that in wild-type GG carriers (95%CI: 1.35-10.67). Moreover, the risk of grade 3-4 delayed diarrhea in homozygous CC carriers of UGT1A1*60 was 20.42 times compared with that in wild-type AA carriers (95%CI: 3.52-118.33). In addition, UGT1A1*28 genetic polymorphism was an independent factor of the occurrence of grade 3-4 neutropenia. The patients with homozygous TA7/7 carriers of UGT1A1*28 had an 1.61 times higher risk of grade 3-4 neutropenia compared with those with wild-type TA6/6 carriers (95%CI: 1.44-12.65). There was no correlation between UGT1A1*93 genetic polymorphism and severe adverse reactions caused by irinotecan. Conclusion: The cancer patients who carried UGT1A1*6, UGT1A1*28 and UGT1A1*60 gene polymorphisms have high risk of severe adverse events caused by irinotecan-based chemotherapy.目的： 探讨恶性肿瘤患者UGT1A1*6、UGT1A1*28、UGT1A1*60和UGT1A1*93基因多态性与伊立替康所致严重不良反应(3～4级迟发性腹泻和中性粒细胞减少)的关系。 方法： 141例采用含伊立替康方案化疗的恶性肿瘤患者，化疗前采集外周静脉血，提取基因组DNA，采用PCR－直接测序法分析UGT1A1*6、UGT1A1*28、UGT1A1*60和UGT1A1*93基因多态性。观察并记录化疗中出现的不良反应，分析基因多态性与伊立替康所致严重不良反应的关系。 结果： 141例患者中，UGT1A1*6 GG、GA和AA基因型分别有71、54和16例，UGT1A1*28 TA6/6、TA6/7和TA7/7基因型分别有105、33和3例，UGT1A1*60 AA、AC和CC基因型分别有52、80和9例，UGT1A1*93 GG、GA和AA基因型分别有105、32和4例。23例发生3～4级迟发性腹泻，56例发生3～4级中性粒细胞减少。多因素logistic回归分析显示，UGT1A1*6和UGT1A1*60的基因多态性是3～4级迟发性腹泻发生的独立影响因素，UGT1A1*6纯合突变型AA携带者发生3～4级迟发性腹泻的风险是野生型GG携带者的3.79倍(95%CI为1.35～10.67)，UGT1A1*60纯合突变型CC携带者发生3～4级迟发性腹泻的风险是野生型AA携带者的20.42倍(95%CI为3.52～118.33)。UGT1A1*28的基因多态性是3～4级中性粒细胞减少发生的影响因素，UGT1A1*28纯合突变型TA7/7携带者发生3～4级中性粒细胞减少的风险是野生型TA6/6携带者的1.61倍(95%CI为1.44～12.65)。UGT1A1*93基因多态性与伊立替康所致3～4级迟发性腹泻和中性粒细胞减少无关。 结论： UGT1A1*6、UGT1A1*28和UGT1A1*60可增加伊立替康所致严重不良反应的发生风险。.