MTHFR基因多态性与晚期结直肠癌患者临床病理特征及预后分析

Relationship between MTHFRgene polymorphism and clinicopathological features and prognosis in patients with advanced colorectal cancer

目的探讨亚甲基四氢叶酸还原酶(MTHFR)基因多态性与晚期结直肠癌(CRC)患者的临床病理特征和预后的关系。方法选取2009-07-31-2018-12-31中国医科大学附属第一医院肿瘤内科收治的晚期CRC患者137例。收集患者的肿瘤组织样品或血液样品。根据提取试剂盒从患者的肿瘤组织和血液中提取DNA。柱色谱法纯化血浆样品,高纯度ctDNA的获得可从磁珠中获得。根据第二代测序原理,对肿瘤细胞DNA、血细胞DNA和ctDNA基因片段进行基因检测,通过对遗传数据分析最终得出基因检测结果。所有患者经病理诊断后确诊结直肠癌的日期作为随访开始的时间。采用χ^(2)或Fisher精确检验分析晚期CRC患者MTHFR基因多态性与性别、年龄、浸润深度、组织学分级、淋巴结转移、T分期、ECOG评分和一线评效之间的关系。Kaplan-Meier曲线和Cox模型评估患者生存。结果晚期CRC患者中MTHFR C677T野生型CC比率为46.7%(64/137),纯合突变型TT比率为21.9%(30/137),杂合突变型CT比率为31.4%(43/137)。MTHFR基因多态性状态与一线评效之间有统计学意义的关联,χ^(2)=6.266,P=0.038。CC型患者的中位生存时间(OS)约34.8个月,高于TT型27.7个月和CT型24.0个月,χ^(2)=0.903,P=0.637,95%CI为26.334~41.266。MTHFR CC型患者无进展生存时间(PFS)约8.9个月,高于TT型7.5个月和CT型5.1个月,χ^(2)=6.057,P=0.048,95%CI为4.877~9.323。将MTHFR TT和CT型患者分为一组,与CC型的PFS 8.9个月相比,TT+CT型的PFS为5.5个月,χ^(2)=4.681,P=0.030,95%CI为4.877~9.323,提示CC型患者可能有更长的PFS。多因素分析显示,MTHFR基因多态性(HR=1.833,95%CI为1.237~2.717,P=0.003)、组织学分级低(HR=1.569,95%CI为1.051~2.341,P=0.028)和一线评效为疾病进展(PD)(HR=3.832,95%CI为2.308~6.363,P<0.001)是影响晚期CRC患者PFS的独立危险因素。结论 MTHFR基因多态性与晚期CRC患者的临床病理特征及预后有关联。MTHFR CC型患者有较长的PFS,MTHFR基因多态性与患者一线评效有关,是PFS的独立危险因素。

Objective To evaluate the association of methylene tetrahydrofolate reductase(MTHFR)gene polymorphism with clinicopathological features and prognosis in patients with advanced colorectal cancer.Methods Patients’blood samples or tumor tissue samples were collected.According to an extraction kit,DNA was extracted from the patient’s tumor tissue and blood.Purified plasma samples by column chromatography,high-purity ctDNA can be obtained from magnetic beads.According to the second-generation sequencing principle,genetic testing was performed on tumor cell DNA,blood cell DNA and ctDNA gene fragments,Finally,we got genetic test results by analyzing the genetic data.The date when all patients were diagnosed with colorectal cancer after pathological diagnosis was taken as the start time of follow-up.When the patients died or by December 31,2018 follow-up was completed.Chi-square test or Fisher exact test was used to analyze the relationship between the polymorphism of MTHFR in patients and the gender,age,depth of invasion,histological grade,Lymph node metastasis,T stage,ECOG score and first-line evaluation in patients with advanced colorectal cancer.The survival of patients was assessed by using Kaplan-Meier curve and Cox model.Results The MTHFR C677 T wild type CC was 46.7%(64/137)in patients with advanced colorectal cancer,homozygous mutation TT was 21.9%(30/137),heterozygous mutation CT was 31.4%(43/137).There was a statistically significant association between MTHFRgene polymorphism status and first-line response,χ^(2)=6.266,P=0.038.The overall survival(OS)of patients with MTHFR CC type was approximately 34.8 months,which was higher than homozygou 27.7 months and heterozygous type 24 months(χ^(2)=0.903,P=0.637,95%CI:26.334-41.266).The progression-free survival time(PFS)of MTHFR CC type was approximately 8.9 months,which was higher than TT type 7.5 months and CT type 5.1 months(χ^(2)=6.057,P=0.048,95%CI:4.877-9.323).The homozygous and heterozygous mutant patients were into one group,compared with the CC type,the PFS of MTHFR was 8.9 months,and the homozygous+heterozygous mutant type was 5.5 months(χ^(2)=4.681,P=0.030,95%CI:4.877-9.323),indicating CC type patients may have longer PFS.In addition,multivariate analysis showed that MTHFRgene polymorphism(HR=1.833,95%CI:1.237-2.717,P=0.003),Histological grade-low(HR=1.569,95%CI:1.051-2.341,P=0.028)and first-line efficacy-PD(HR=3.832,95%CI:2.308-6.363,P<0.001)were independent risk predictors for the PFS of advanced colorectal cancer patients.Conclusions MTHFRgene polymorphisms is related to the clinicopathological characteristics and prognosis of patients with advanced colorectal cancer.The patients with MTHFR wild-type have longer progression-free survival,MTHFR gene polymorphism is related to the first-line efficacy of patients,is independent risk predictor for the PFS.