UGT1A1基因多态性在FOLFIRI方案二线治疗转移性结直肠癌中的临床意义

Clinical significance of UGT1A1 gene polymorphisms on FOLFIRI regimen as second-line treatment in metastatic colorectal cancer

目的 探讨尿苷二磷酸葡萄糖醛酸转移酶（UGT） 1A1基因多态性在FOLFIRI方案二线治疗转移性结直肠癌（mCRC）中的安全性和作为疗效预测指标的价值.方法 在FOLFIRI方案化疗前分离mCRC患者外周血中单核细胞,采用荧光定量PCR-HRM法测定UGT1A1基因型.根据NCI CTC 3.0和RECIST 1.0标准分别评价化疗的不良反应和疗效,并分析UGT1 A1基因多态性与不良反应和近期有效率（RR）的关系.用Kaplan-Meier法进行生存分析,Log-rank检验分析UGT1A1基因型对无进展生存期（PFS）的影响.结果 38例患者中,UGT1A1＊ 28位点的野生型（TA6/6）有31例（81.6％）,杂合突变型（TA6/7）2例（5.3％）,纯合突变型（TA7/7）5例（13.2％）;UGT1A1＊6位点的野生型（G/G）有28例（73.7％）,杂合突变型（G/A）8例（21.1％）,纯合突变型（A/A）2例（5.3％）.在3～4级延迟性腹泻和中性粒细胞减少的发生率方面,UGT1A1＊28的野生型（TA6/6）显著低于TA6/7和TA7/7基因型（P＜0.05）,UGT1A1＊6的野生型（G/G）也显著低于G/A和A/A基因型（P＜0.05）.RR和PFS在UGT1A1各种基因型之间差异无统计学意义（P＞0.05）.结论 在FOLFIRI方案二线治疗mCRC中,UGT1A1＊ 28位点和UGT1A1 ＊6位点突变可以作为严重的延迟性腹泻和中性粒细胞减少的预测指标,但UGT1A1基因多态性与疗效无关.

Objective To investigate uridine diphosphate glucuronosyltransferase（UGT） 1A1 gene polymorphism as the predictor of safety and efficacy of FOLFIRI regimen as second-line treatment in metastatic colorectal cancer（mCRC） patients.Methods Peripheral blood mononuclear cells form the mCRC patients were separated before FOLFIRI chemotherapy and the UGT1 A1 genotypes were determined by the fluorescence quantitative PCR-HRM method.The side effects and tumor response were evaluated using NCICTC 3.0 and RECIST 1.0 criterion,respectively.The correlation between UGT1A1 gene polymorphisms and side effects or objective response rate（ORR） was subsequently analyzed.Progression free survival（PFS） was recorded and survival analysis was carried out by Kaplan-Meier method for the impact of genotypes on PFS.Results The UGT1A1 genotypes in 38 consecutive patients were as follows：UGT1 A1 ＊ 28 homozygous wild-type TA6/6 （31 cases,81.6%）,heterozygous mutant-type TA6/7 （2 cases,5.3%）,homozygous mutant-type TA7/7（5 cases,13.2%）; UGT1A1 ＊ 6 wild-type G/G（28 cases,73.7%）,heterozygous mutant-type G/A（8 cases,21.1%）,homozygous mutant-type A/A（2 cases,5.3%）.For the incidence rate of grade 3 to 4 delayed diarrhea and neutropenia,the rates were significantly lower in patients of UGT1A1 ＊ 28 TA6/6 wide-type genotype than those of TA6/7 and TA7/7 mutant-type genotypes（P 〈0.05）.The rate was significantly lower in patients of UGT1A1 ＊ 6 G/G genotype than that of G/A and A/A mutanttype genotypes （P 〈 0.05）.No significant difference of either ORR or PFS was observed among different genotypes （P 〉 0.05）.Conciusion For FOLFIRI regimen as second-line chemotherapy in mCRC patients,the UGT1A1 ＊ 28 and UGT1A1 ＊ 6 locus mutations can be regarded as predictors for irinotecan-associated severe delayed diarrhea and neutropenia,whereas no association between UGT1 A1 gene polymorphism and efficacy is observed.