消化道肿瘤患者MTHFR 基因多态性与5- 氟尿嘧啶化疗不良反应的相关性研究

目的　在消化道肿瘤患者中，探讨MTHFR 1298A>C 和MTHFR 677C>T 基因多态性与5- 氟尿嘧啶（5-FU） 化疗出现不良反应的关系。方法　2016 年2~6 月，入组复旦大学附属中山医院肿瘤内科收治的123 例消化道肿瘤患 者。提取外周血中的基因组DNA，通过Sanger 测序检测MTHFR 1298A>C 和MTHFR 677C>T 的基因型。随访其中 98 例含5-FU 治疗方案的患者，分析了不同基因型的患者发生毒副反应的类型及严重程度的区别。结果　123 例消化道 肿瘤患者中，MTHFR 1298A>C 野生型 76 例（61.79%），杂合型AC 40 例（32.52%），纯合型CC 7 例（5.69%）。 MTHFR677C>T 野生型CC 50 例（40.65%）， 杂合型CT 61 例（49.59%）, 纯合型TT 12 例（9.76%）。98 例化疗 方案中含5-FU 的患者中，MTHFR 677C>T 突变型（CT 和TT）显著增加化疗后发生不良反应的风险（χ2=4.188， P<0.05）；MTHFR 1298A>C 突变型（AC 和AA）、性别、年龄、治疗方案与使用5-FU 产生的相关毒副作用无显著关 联性。结论　在接受5-FU 治疗的消化道肿瘤患者中，MTHFR 677C>T 多态性显著增加化疗相关毒副反应的发生风险， 该基因可能成为预测氟尿嘧啶类化疗药物发生临床不良事件的风险因素，能够为临床选择合适的治疗方案提供更多的信 息。

Relationship between MTHFR Gene Polymorphisms and Adverse Events by 5-FU in Gastrointestinal Cancer

Objective　To investigate the relationship of MTHFR 677C>T and MTHFR 1298A>C gene polymorphisms in 5-fluorouracil (5-FU)-based chemotherapy in gastrointestinal cancer. Methods　From February 2016 to June 2016, 123 gastrointestinal cancer patients were admitted to Zhongshan Hospital of Fudan University. Genomic DNA in peripheral blood was extracted, and MTHFR 1298A>C, MTHFR677C>T gene polymorphisms were detected by Sanger sequencing. A total of 98 patients treated with 5-FU were chosen to observe the adverse events during chemotherapy, and the differences between the adverse event and grades in patients with different genotypes was analyzed. Results　Of the 123 patients, MTHFR 1298A>C wild type AA was 76 (61.79%), heterozygous AC was 40 (32.52%) and homozygous CC was 7 (5.69%). MTHFR 677C>T wild type CC was 50 cases (40.65%), heterozygous type CT was 61 cases (49.59%) and homozygous type TT 12 was cases (9.76%). In the 98 gastrointestinal Cancer cases, the incidence of total the incidence of adverse events in the patients carrying the MTHFR 677C>T (CT+TT) genotype was higher than in the WT genotype (CC) (P<0.05). The MTHFR 1298A>C genotype, sex, age and chemotherapy strategy were not associated with the adverse events inducing by 5-FU. Conclusion　The MTHFR 677C>T polymorphism significantly increases the risk of chemotherapy-related adverse reactions in gastrointestinal cancer patients treated with 5-FU.The applying of MTHFR polymorphism may be used as a risk factor for predicting clinical adverse events in fluorouracil-based chemotherapy and assist the individualized treatment in gastrointestinal cancer.