UGT1A1基因多态性与伊立替康治疗结直肠癌不良反应的关系

Relationship between UGT1A1 gene polymorphisms and toxicity of irinotecan-based chemotherapy in colorectal cancer

背景与目的:尿苷二磷酸葡萄糖醛酸转移酶1A1(uridine diphosphoglucu-ronosyl transferase 1A1,UGTlA1)是伊立替康代谢关键酶,其活性受基因多态性影响显著。本研究探讨结直肠癌患者中,UGT1A1*28和UGT1A1*6基因多态性与伊立替康治疗相关不良反应之间的关系。方法:入组2013年4月—2013年12月于复旦大学附属中山医院肿瘤内科接受治疗的消化道恶性肿瘤患者160例。抽提外周血中基因组DNA,分别采用STR方法和Sanger测序法,检测UGT1A1*28和UGT1A1*6基因型,分析UGT1A1基因多态性分布情况。对其中82例化疗方案中含伊立替康的结直肠癌患者进行随访,记录不良反应发生情况和严重程度,比较不同基因型患者之间的差异。结果:160例消化道肿瘤患者中,UTG1A1*28(启动子TATA盒区域TA重复次数)野生型TA6/6124例(77.5%);杂合子TA6/7 33例(20.5%);纯合子TA7/7 3例(2.0%)。UGT1A1*6位点(211G>A)野生型GG 105例(65.6%),杂合子GA 48例(30.0%);纯合子AA 7例(4.4%)。82例化疗方案中含伊立替康的结直肠癌患者中,*28基因型(TA6/7和TA7/7)显著增加发生3级以上中性粒细胞减少的风险(58.3%vs 0.0%,P<0.001),并增加整体不良反应发生率(76.0%vs 45.6%,P<0.001);*6基因型(GA和AA)、年龄、性别、化疗方案和伊立替康相关不良反应发生无显著相关性。结论:接受伊立替康化疗的结直肠癌患者,UGT1A1*28位点多态性显著增加中性粒细胞减少发生的风险,可预测伊立替康引起的骨髓抑制性不良反应,辅助临床选择合适的化疗方案。

Background and purpose： Uridine diphosphoglucu-ronosyl transferase 1A1 （UGT1A1） is an important enzyme for metabolism of irinotecan. The activity of UGT1A1 enzyme was significantly affected by the gene polymorphism. This study aimed to investigate the correlation of UGT1A1＊28 and ＊6 gene polymorphisms with irinotecan-based chemotherapy in colorectal cancer（CRC）. Methods： Analysis of UGT1A1＊28 and ＊6 gene polymorphisms was performed in 160 gastrointestinal cancer patients admitted to Zhongshan Hospital Fudan University from Apr. 2013 to Dec. 2013 by amplifying the gene fragments using PCR, STR and Sanger sequencing. Eighty-two cases with CRC treated with irinotecan were chosen to observe the adverse events during chemotherapy. The incidence of different genotypes was compared. Results：The distribution of the genotypes in 160 gastrointestinal cancer patients was as followed：UGT1A1＊28 wild-type genotype TA6/6 （124, 77.5%）, heterozygous genotype TA6/7 （33, 20.5%）, and homozygous genotype TA7/7 （3, 2.0%）;UGT1A1＊6 wild-type genotype GG （105, 65.6%）, heterozygous genotype GA （48, 30.0%）, and homozygous genotype AA （7, 4.4%）. In the 82 CRC cases, the incidences of grade 3 and 4 neutropenia in the patients carrying UGT1A1＊28 （TA6/7＋TA7/7 ） were higher than those in the WT genotype （TA6/6） （58.3%vs 0.0, P〈0.001）, and increased the total incidence of adverse events （76.0%vs 45.6%, P〈0.001）. There was no signiifcant relevance between UGT1A1＊6 genotype, age, gender chemotherapy and adverse events. Conclusion：In the CRC cases with irinotecan-based chemotherapy, the UGT1A1＊28 （TA6/7＋TA7/7） genotype signiifcantly increased the risk of grade 3 and 4 neutropenia. Detecting UGT1A1 gene polymorphisms may guide individualized treatment and predict adverse events.