UGT1A1基因不同表型与FOLFIRI方案治疗晚期结直肠癌疗效及毒副反应的相关性

目的:回顾性分析UGT1A1基因不同表型与FOLFIRI方案治疗晚期结直肠癌疗效及毒副反应的相关性。方法:收集贵州医科大学附属肿瘤医院腹部肿瘤科2014年1月至2018年12月收治的临床分期为Ⅳ期结直肠癌或根治性手术后复发转移的晚期结直肠癌患者240例的临床病理资料，所有患者初次行FOLFIRI方案化疗前抽血，提取全血中的DNA，采用PCR技术行UGT1A1基因型检测；接受FOLFIRI化疗方案治疗直至疾病进展或者发生不可耐受的毒性反应。分别采用Binary Logistic Regression模型分析UGT1A1基因不同表型与FOLFIRI化疗疗效的相关性，分解模型及广义估计方程多应变量回归分析UGT1A1基因不同表型与FOLFIRI化疗毒副反应的相关性。结果:本组患者共发现3种UGT1A1基因表型，分别为UGT1A1*1/*1(纯合野生型TA6/6型 188/240 78.3%)、UGT1A1*28/*1(杂合突变型TA6/7型 47/240 19.6%)和UGT1A1*28/*28(纯合突变型TA7/7型 5/240 2.1%)。UGT1A1基因型中TA6/7型TA6/6型相比，FOLFIRI化疗无应答风险增加16%，但无统计学差异；本组转移器官＞2个的患者中TA6/7型和TA6/6型相比，血液学及非血液学毒副反应发生的风险均增加了9.377 3倍（P=0.007 9），其中消化道毒副反应发生风险增加了42.806 6倍（P=0.025 9）；本组行FOLFIRI化疗≥4周期的患者中，TA6/7型比TA6/6型的患者发生血液学毒性的风险增加了22.324 6倍（P=0.003 5）。结论:TA6/6型为我省结直肠癌患者最为常见的UGT1A1基因表型，而TA7/7型罕见；晚期结直肠癌转移器官数超过2个行FOLFIRI化疗的患者中UGT1A1基因TA6/7型较TA6/6型患者血液学及非血液学毒副反应发生的风险均明显增加，其中消化道毒副反应发生的风险更胜。

Correlation between different phenotypes of UGT1A1 gene and FOLFIRI regimen in the treatment of advanced colorectal cancer

Objective:To analyze the correlation between the different phenotypes of UGT1A1 gene and the efficacy and toxic side effects of FOLFIRI regimen in the treatment of advanced colorectal cancer,in order to provide individualized treatment under genetic guidance.Methods:The clinical and pathological data of 240 patients with advanced colorectal cancer who underwent IV stage colorectal cancer or recurrence after radical surgery from January 2014 to December 2018 in the department of abdominal oncology,Affiliated Tumor Hospital of Guizhou Medical University,were collected.The FOLFIRI protocol was used to extract DNA from whole blood before chemotherapy,and the UGT1A1 genotype was detected by PCR.The FOLFIRI chemotherapy regimen was used until the disease progressed or an intolerable toxicity occurred.The Binary Logistic Regression model was used to analyze the correlation between the different phenotypes of UGT1A1 gene and FOLFIRI chemotherapy.The decomposition model and the generalized estimation equation multivariate regression analysis were used to analyze the correlation between the different phenotypes of UGT1A1 gene and FOLFIRI chemotherapy.Results:Three UGT1A1 gene phentypes were found,including UGT1A1*28/*1 (heterozygous mutant type TA6/7,47/240,19.6%) and UGT1A1*28/*28 (homozygous mutant type TA7/7,5/240,2.1%).Compared with TA6/7 and TA6/6,the risk of non-response to FOLFIRI chemotherapy increased by 16%,but there was no statistical difference.Compared with TA6/7 and TA6/6 in patients with more than 2 metastatic organs,the risk of hematologic and non-hematologic toxic and side effect increased by 9.377 3 times (P=0.007 9),including side effects of digestive tract,and the risk increased by 42.806 6 times (P=0.025 9).In patients with FOLFIRI chemotherapy greater than 4 cycles,the risk of hematologic toxicity was increased by 22.324 6 times in patients with TA6/7 compared with TA6/6 (P=0.003 5).Conclusion:TA6/6 is the most common UGT1A1 gene phenotype in patients with colorectal cancer in our province,while TA7/7 is rare.In patients with advanced colorectal cancer with more than 2 metastatic organs undergoing FOLFIRI chemotherapy,the risk of hematological and non-hematologic toxic and side effect is significantly increased in patients with TA6/7 type compared with TA6/6 type,and the risk of digestive tract is more significant.