结直肠癌中MDR1和ABCG2基因多态性与伊立替康疗效及不良反应的关系

Correlation of MDR1 and ABCG2 genetic polymorphisms with the efficacy and adverse events of irinotecan chemotherapy in patients with colorectal cancer

目的研究MDRl和ABCG2基因单核苷酸多态性（SNP）与结直肠癌患者伊立替康（CPT-11）化疗疗效及不良反应的关系。方法回顾性收集北京大学肿瘤医院消化肿瘤内科1996年1月至2011年12月行以CPT．11为基础化疗药物的晚期结直肠癌患者的完整临床资料及血液样本，提取血液DNA，用直接测序法检测MDRl和ABCG2基因SNP．分析基因多态性与CPT-11疗效和不良反应的相关性。结果MDR12677G〉T／A及ABCG2421C〉A、34G〉A和376C〉T的血标本及肿瘤组织检测SNP结果一致率高，分别为94．4％（34／36）、94．6％（35／37）、95．0％（38／40）和97．2％（35／36）。MDR12677G〉T／A中，野生型（G／G）患者较突变型患者临床获益率高．但差异无统计学意义（P〉0．05）；且在二线化疗的患者中，野生型患者无进展生存期（PFS）明显优于突变型患者（P=0．012）。未观察到ABCG2421C〉A、34G〉A和376C〉T多态性与化疗疗效有相关性（均P〉0．05）。同时，未观察到MDR12677G〉T／A、ABCG2421C〉A、ABCG234G〉A和ABCG2376C〉T多态性与患者3度以上粒细胞减少及腹泻相关。结论在晚期结直肠癌患者中，MDR12677G〉T／A可能作为分子标记物来预测伊寺替康方案化疗疗效。

Objective To investigate the correlation of MDR1 and ABCG2 genetic polymorphisms with the efficacy and adverse events of irinotecan chemotherapy in patients with colorectal cancer （CRC）. Methods Clinical data of CRC patients treated with irinotecan-based chemotherapy in the Peking University Cancer Hospital between January 1996 and December 2011 were collected, and their blood samples were collected accordingly. Genomie DNA was extracted from blood samples. The following SNP detection of MDRI and ABCG2 genes was conducted by direct sequencing method. The correlation of genetic SNPs with efficacy and toxicity of irinotecan treatment was further analyzed. Results Allele frequencies of MDR1 2677 G〉T/A, ABCG2 421 C〉A, 34 G〉A, 376 C〉T were comparable with previous studies. Genetic SNPs results from peripheral blood samples and tumor tissues were highly consistent. Patients carrying MDR1 2677 wild type had higher clinical benefit than those carrying mutant genotype, while the differences were not significant. The progression-free survival （PFS） was longer in wild-type patients as compared to mutant-type patients in second-line chemotherapy （P=0.012）. There were no significant correlations between ABCG2 421 C〉A, 34 G〉A, 376 C〉T and chemotherapy efficacy. No significant correlations were observed between MDR1 2677 G〉T/A, ABCG2 421 C〉A, ABCG2 34 G〉A, ABCG2 376 C〉T and irinotecan-related grade 3 and 4 neutropenia or diarrhea. Conclusion MDR1 2677 G〉T/A may be served as a biomarker in predicting the efficacy of irinotecan chemotherapy in patients with colorectal cancer.