MTHFR、GSTP1、MSH3和ABCG1单核苷酸多态性与结直肠癌辅助化疗疗效和不良反应的相关性研究

Relationship of single nucleotide polymorphisms of MTHFR, GSTP1, MSH3 and ABCG1 with the efficacy and adverse reactions of adjuvant chemotherapy in colorectal cancer patients

目的探讨R0切除结直肠癌(colorectal cancer,CRC)患者MTHFR、GSTP1、MSH3和ABCG1单核苷酸多态性(single nucleotide polymorphisms,SNPs)与术后辅助化疗疗效和不良反应的关系。方法收集2010年8月至2012年3月在河南省肿瘤医院行R0切除的42例CRC患者,术后均接受mFOLFOX6或XELOX方案化疗,并在化疗前收集血样,应用Sanger测序法检测42例CRC患者MTHFR-rs1801131、GSTP1-rs1695、MSH3-rs863221和ABCG1-rs425215的基因型,所有患者术后随访5年,分析各位点基因多态性与患者预后及化疗相关不良反应的关系。结果仅MTHFR-rs1801131多态性与预后相关,MTHFR-rs1801131 AA基因型患者中位(disease-free survival,DFS)和(overall survival,OS)均显著长于AC/CC基因型(25个月vs 6.5个月,P=0.012;44.7个月vs 15.2个月,P=0.010)。GSTP1-rs1695多态性与胃肠道不良反应有关,AA基因型患者Ⅱ级及以上胃肠道不良反应发生率远高于AG/GG基因型(25.0%vs 0,P=0.040)。MSH3和ABCG1多态性与预后和不良反应之间无明显相关性。结论 MTHFR-rs1801131突变是R0切除CRC者辅助化疗效果较差的独立预测因子,GSTP1-rs1695突变患者化疗期间发生胃肠道不良反应更低。

Objective To investigate the predictive value of SNPs in MTHFR, GSTP1, MSH3 and ABCG1 of colorectal cancer (CRC) patients in effect and toxicity of adjuvant chemotherapy. Methods A total of 42 CRC patients who had received surgery in our hospital from Aug. 2010 to Mar. 2012 were selected. All patients were treated with mFOLFOX6 or XELOX regimen and blood samples were collected before chemotherapy. Sequencing method was used to detect genotypes of MTHFR-rs1801131, GSTP1-rs1695, MSH3-rs863221 and ABCG1-rs425215. Association between SNPs and survival and toxicity was assessed. Results Only MTHFR-rs1801131 polymorphism was associated with survival. Both of the median DFS and OS of patients with MTHFR rs1801131 AA genotype were significantly longer than AC/CC genotype (25 months vs 6.5 months, P =0.012;44.7 months vs 15.2 months, P =0.010). Incidence of above Ⅱ grade gastrointestinal toxicity in patients with GSTP1 rs1695 AA genotype was much higher than AG/GG genotype (25.0% vs 0, P =0.040). No significant correlation was found between adverse reactions and SNPs in MTHFR/MSH3/ABCG1. Conclusion Mutation in MTHFR-rs1801131 is a risk factor in prognosis of CRC patients undergoing adjuvant chemotherapy and GSTP1-rs1695 polymorphism is a potential marker in predicting gastrointestinal tract adverse reactions during treatment.