亚甲基四氢叶酸还原酶和胸苷酸合成酶基因多态预测氟尿嘧啶为基础化疗方案治疗晚期胃癌疗效关系的研究（英文）

Polymorphism in the Methylenetetrahydrofolate Reductase and Thymidylate Synthase Gene Predicts for Response to Fluorouracil-based Chemotherapy in Advanced Gastric Cancer Patients

目的观察亚甲基四氢叶酸还原酶(MTHFR)(C677T、A1298C)和胸苷酸合成酶(TS 3'-UTR)多态与5-FU为基础化疗方案及晚期胃癌敏感性的关系。方法选取173例晚期胃癌患者,所有病例均接受5-FU为基础化疗方案(FOLFOX,FP和DCF方案)化疗。在化疗前获取外周血白细胞DNA。采用PCR-RELP检测基因型。在2个基因中共检测了9种遗传多态。173例中检测了MTHFR(C677T、A1298C)和TS(3'-TUR)多态。结果所有患者化疗总有效率为35.8%。DCF方案的有效率显著高于FP和FOLFOX方案(55.8%vs 27.1%,31.1%;P=0.006)。MTHFR C677T T/T基因型患者的有效率显著高于C/C和C/T基因型(73.3%vs 28.0%;P=0.000)。在MTHFR A1298C中,A/A基因型患者的有效率显著高于C/C和A/C基因型(41.8%vs 21.6%,P=0.011),在TS 3'-UTR中,-6/-6bp和-6/+6bp基因型患者的有效率显著高于+6/+6 bp基因型(40.3%vs 17.6%,P=0.014)。FOLFOX和FP方案中,MTHFR C677T T/T基因型患者的有效率均显著高于C/C和C/T基因型(P=0.008;P=0.000),但在DCF方案中没有发现差异。在MTHFR C/T和C/C基因型中,DCF方案的有效率显著高于FP和FOLFOX方案(P=0.000)。MTHFR C677T T/T基因型患者的Ⅲ-Ⅳ度呕吐(66.7%)和口腔炎(30.0%)发生率显著高于C/C和C/T基因型(41.3%,9.8%;P=0.011,0.003)。MTHFR A1298C A/A基因型患者的Ⅲ-Ⅳ度口腔炎(17.2%)和腹泻(13.9%)发生率同样显著高于A/C和C/C基因(3.9%,2.0%;P=0.025,0.026)。TS 3'-UTR的不同多态之间没有发现毒性差异。结论检测外周血白细胞DNA中的MTHFR和TS基因多态能预测以5-FU为基础化疗方案治疗晚期胃癌的有效性和化疗相关的毒性反应。

Background ＆ Aims Fluorouracil （5-FU） is widely used in the treatment of gastric cancer. Methylenetctrahydrofolate reductase （MTHFR） and thymidylate synthetase （TS） are important targets of many anti-metabolitcs, including 5-FU. The aim of the present study is to investigate the relationship between polymorphism in the MTHFR （C677T, A1298C） and TS （3＇-UTR） genotypes and sensitivity of gastric cancer to 5-FU- based chemotherapy. Methods 173 patients of advanced gastric cancer were analyzed. All patients were treated with 5-FU-based chemotherapy （FOLFOX, FP and DCF regimen）. DNA from peripheral blood leukocytes was obtained before therapy. All genotypes were detected by PCR-RFLP. 9 germline polymorphisms within 2 genes were analyzed. The genotypes of MTHFR （C677T, A1298C） and TS （3＇-TUR） were analyzed in 173 patients. Results The overall response rate （RR） was 35.8%. The RR of the DCF regimen group was significantly higher than that of the FP and FOLFOX regimen groups （55.8% vs 27.1% , 31.1% ; P =0. 006）. The RR of the MTHFR C677T T/T genotype was significantly higher than that of the C/C and C/T genotypes （73.3% vs 28.0% ; P =0. 000）. In MTHFR A1298C, a higher RR was observed in A/A genotype compared with the C/C and A/C genotypes （41.8% vs 21.6%, P = 0. 011 ）. The RR of the -6/-6 bp and -6/＋ 6 bp genotypes in TS 3＇-UTR was significantly higher than that of the ＋6/＋6 bp genotype （40.3% vs 17.6%, P = 0. 014）. The RR of the MTHFR C677T T/T genotypes in the FOLFOX or FP regimens was significantly higher than that of the C/C and C/T genotypes （P = 0. 008 ; P = 0. 000）, but no difference in the DCF regimen. The RR of DCF regimen was significantly higher than that of the FOLFOX and FP regimens in the C/T and C/C genotypes （P = 0.000）. The MTHFR C677T T/T genotypes had a significantly higher incidence of grade 3/4 emesis （66.7%） and stomatitis （30.0%） than patients with the C/T or C/C genotypes （41.3% , 9.8% ; P = 0.011, 0.003）. The MTHFR A1298C A/A genotype had a higher incidence of grade 3/4 stomatitis （ 17.2% ） and diarrhea （ 13.9% ） than patients with A/C and C/C genotypes （3.9%, 2.0% ; P = 0. 025, 0. 026 ）. There was no difference in toxicity for patients with the TS 3＇-UTR genotypes. Conclusions Our studies indicated that detection of MTHFR and TS polymorphism can be used to guide the choice of 5-FU based chemotherapy on advanced gastric cancer.