UGT1A1基因多态性与转移性结直肠癌伊立替康化疗毒性及疗效的关系

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

目的:探讨UGT1A1*28和UGT1A1*6基因多态性与伊立替康治疗转移性结直肠癌患者的不良反应和疗效之间的关系。方法:外周血中抽提基因组DNA,采用PCR扩增目的基因片段,直接测序法分析2010年4月至2012年3月在我院做基因检测的207例消化道肿瘤患者UGT1A1*28和UGT1A1*6基因多态性的分布情况,并对其中56例采用含伊立替康方案化疗的转移性结直肠癌患者出现的不良反应情况、肿瘤进展时间及化疗疗效进行观察并记录,比较不同基因型患者之间的差异。结果:207例消化道肿瘤患者中,UGT1A1*28位点野生型TA6/6有164例(79.2%),杂合突变型TA6/7有41例(19.8%),纯合突变型TA7/7有2例(1.0%);UGT1A1*6位点野生型G/G有154例(74.4%),杂合突变型G/A有51例(24.6%),纯合突变型A/A有2例(1.0%)。在56例转移性结直肠癌患者中,*6位点突变型(G/A和A/A)可以增加发生3级以上腹泻(38.9%vs 7.9%,P<0.05)和中性粒细胞减少(61.1%vs 29.0%,P<0.05)的风险;*28位点突变型(6/7和7/7)可以增加发生3级以上血小板减少(33.3%vs 2.1%,P<0.05)的风险;肿瘤进展时间和化疗疗效在*28和*6位点各基因型之间差异无统计学意义。结论:在采用含伊立替康方案化疗的转移性结直肠癌患者中,UGT1A1*6位点突变型增加发生3级以上腹泻和中性粒细胞减少的风险;UGT1A1*28位点突变型增加发生3级以上血小板减少的风险。

AIM ： To investigate the corretion of UGT1AI ＊ 28 and UGT1A1 ＊ 6 gene polymorphisms with irino- tecan - associated adverse events and efficacy in the patients with metastatic colorectal cancer （mCRC） treated with irinote- can- based chemotherapy. METHODS： Analysis of UGT1A1 ＊28 and UGTIA1 ＊6 gene polymorphisms was performed in 207 gastrointestinal cancer patients admitted to our hospital from April 2010 to March 2012 by amplifying the gene frag-ents using PCR and direct sequencing. Fifty six cases with mCRC treated with ifinotecan were chosen to observe the ad verse events and efficacy during chemotherapy, and the time to progression （T/P） was also recorded. The incidence of different gcnotypes was compared. RESULTS ： The distribution of the genotypes in 207 gastrointestinal cancer patients was as follows： UGT1A1 - 28 wild - type （WT） genotype TA6/6 （ 164, 79.2% ）, heterozygous genotype TA6/7 （41, 19.8% ）, and homozygous genotype TA7/7 （2, 1.0% ） ; UGTIA1 ＊ 6 WT genotype G/G （ 154, 74.4% ）, heterozygous genotype G/ A （51, 24.6% ）, and homozygous genotype A/A （2, 1.0% ）. In the 56 mCRC cases, the incidence of grade 3 and 4 de- layed diarrhea and neutropenia in the patients carrying UGT1A1 ＊6 （G/A and A/A） was higher than that in the WT geno- type （6/6） （38.9% vs 7.9% ,61. 1% vs 29.0%, both P〈0.05）. The incidence of grade 3 and 4 thrombocytopenia in the patients carrying UGT1A1 ＊ 28 （TA6/7 and TA7/7） was higher than that in the WT genotype （TA6/6） （33. 3% vs 2. 1%, P 〈 0.05 ）. No significant difference of TYP and chemotherapeutic effect was observed between different genotypes. CONCLUSION： The UGT1A1 ＊6 （G/A and A/A） genotypes increase the risk of grade 3 and 4 delayed diarrhea and neu- tropenia, and the UGTIA1 ＊ 28 （TA6/7 and TA7/7 ） genotypes increase the risk of grade 3 and 4 thromlx^cytopenia in mCRC patients treated with irinotecan -based chemotherapy.