UGTlA1基因启动子多态性与伊立替康化疗毒性作用的关系

Study of irinotecan-induced toxicity and its correlation to UGT1A1 gene promoter polymorphisms

目的初步了解宫颈癌和卵巢癌患者血中尿苷二磷酸葡萄糖醛酸转移酶1A1（UGTlAl）基因启动子的多态性情况，并研究其多态性与伊立替康化疗的毒性作用（延迟性腹泻、中性粒细胞减少）的关系。方法收集64例使用伊立替康联合顺铂方案化疗的宫颈癌和卵巢癌患者的全血标本，提取基因组DNA，PCR扩增UGTlAl基因启动子，用毛细管电泳等位基因片段分析方法分析UGTlAl基因启动子的多态性，并与化疗毒性作用进行相关性分析。结果64例患者中UGTIAl基因启动子的野生纯合型（TA6／6基因型）最为常见，共44例，占69％（44／64）；其次为突变杂合型（TA6／7基因型），共17例，占27％（17／64）；突变纯合型（TA7／7基因型）仅3例，占5％（3／64）。UGTlAl基因启动子基因型是发生延迟性腹泻的独立影响因素（OR=4．228，95％c，为1．065-16．785，P=0．040），但不是中性粒细胞减少发生的独立影响因素（OR=3．659，95％CI为0．911～14．700，P=0．068）：TA6／7和TA7／7基因型比TA6／6基因型患者发生中性粒细胞减少、延迟性腹泻的风险高（P均=0．001）。结论在宫颈癌、卵巢癌患者中，UGTlAl基因启动子以TA6／6基因型较常见。UGTlAl基因启动子多态性是伊立替康所致延迟性腹泻的独立影响因素，TA6／7和TA7／7基因型患者发牛延迟性腹泻的风险高于TA6／6基因型。

Objectives To investigate the distribution of uridine diphosphate-glucuronosyltransferase 1A1 （UGT1A1） gene promoter polymorphism and its relation to the toxicities caused by irinotecan in Chinese patients with cervical cancer and ovarian cancer. Methods Sixty-four blood samples were taken from the patients with ovarian cancer and cervical cancer. The DNA was extracted and amplified with PCR. Then, the sequences of UGT1A1 gene promoter were detected by capillary electrophoresis allele fragment analysis （size-based analysis） methods. The relationship between UGT1A1 gene promoter polymorphism and the toxicity caused by irinotecan was analyzed. Results In all the patients, TA 6/6 was the most common genotype of UGT1 A1 gene promoter （44 cases） , accounting for 69% （44/64）, followed by genotype of TA 6/7 （17 cases, 27%, 17/64）, while genotype TA 7/7 was rare （3 cases, 5%, 3/64）. The genotypes of UGT1A1 gene promoter was an independent factor for the occurrence of delayed diarrhea （P = O. 040, OR = 4. 228, 95% CI： 1. 065 - 16. 785 ） but not for neutropenia （ P -- 0. 068, OR = 3. 659, 95% CI：O. 911 - 14. 700）. The patients with both genotype TA 6/7 and TA 7/7 presented much higher risk of delayed diarrhea and neutropenia than those with TA 6/6 （ all P = O. 001 ）. Conclusions UGT1 A1 gene promoter polymorphism may be a significant influencing factor for delayed diarrhea. The patients with both genotype TA 6/7 and TA 7/7 could present much higher risk for delayed diarrhea than those with TA 6/6, while genotype TA 6/6 may be the most common UGT1A1 promoter type in Chinese patients with cervical or ovarian cancer.