Study On Correlations Between MRNA Expression Levels/Polymorphisms Of TS,ERCC1 And Chemotherapy/Prognosis In Patients With Ⅲ/Ⅳ Stage Colorectal Cancer

Backgrounds:Currently, for the patients with unresectable stge III and IV colorectal cancer, we usually take combined therapy based on chemotherapy.FOLFOX regimen(5-fluorouracil+oxaliplatin+leucovorin) is one of the first-line treatments of colorectal adenocarcinoma. FOLFOX regimen to some extent prolongs the overall survival of patients with colorectal cancers. However, patients might undergo different situations or different degrees of side effects during or after chemotherapy, a number of patents also do not benefit from chemotherapy. Therefore, it is necessary to replace the conventional experience chemotherapy based only on histological type and pathological stage with individualized chemotherapy guided by molecular diagnostic techniques. According to the different molecular subtypes of colorectal adenocarcinoma, we should select different chemotherapeutic regimens which could reduce the side effects of chemotherapy on the basis of prolonging the survival of patients, so the patients with III or IV stage colorectal cancers could obtain maximum benefit. The main purpose of this study was to analyze the correlation between TS/ERCC1 mRNA expression levels and chemotherapy/prognosis of patients with stage III or IV colorectal cancers treated with first-line FOLFOX4 regimen, in the mean time to analyze the correlation between TS/ERCC1 gene polymorphisms and the chemotherapy/prognosis of patients.Method:Select 80 cases of patients with stage III or IV colorectal cancers certified by pathology and imaging treated with FOLFOX4 regimen from January 2009 to December 2015. Specific regimens:oxaliplatin 85mg/m2.d, IV gtt 2h, Di; leucovorin 400mg/m2.d, IV gtt 2h, D1-2; 5-FU 400mg/m2,Ⅳ bolus, D1-2, then 5-FU 600mg/m2,CIV 22h,14 days for a period. Patients should undergo 6 to 12 periods of chemotherapy until tumor progression, refused chemotherapy, severe adverse reactions. The follow-up treatment is to apply symptomatic and supportive treatment or to switch to FOLFIRI chemotherapy. Extract peripheral blood of the patients to test polymorphisms of TS gene and ERCCl gene, in the mean time bite tumor samples by colonoscopy to test the expression levels of TS mRNA and ERCC1 mRNA by the real-time fluorescence quantitative PCR technique.Results:The overall response rate(ORR) is 44.44%. There is statistical differences in theincidences of bone marrow suppression and diarrhea between low expression of TS mRNA group and high expression of TS mRNA group (X2=5.772,9.230, P=0.016,0.002; P< 0.05). The median TTP of the patients with low expression of TS mRNA is 6 months and the median TTP of the patients with high expression of TS mRNA is 4 months. The media OS of the patients with low expression of TS mRNA is 28 months and the media OS of the patients with high expression of TS mRNA is 13 months. By studying the correlations between TS mRNA expression and TTP/OS, statistical differences of TTP and OS are observed between the patients with low exprssion of TS mRNA and the patients with high exprssion of TS mRNA (P=0.013,0.008; P<0.05). There is statistical differences in the incidences of diarrhea and skin pigmentation between low expression of ERCC1 mRNA group and high expression of ERCC1 mRNA group (X2=9.757,3.999; P=0.002,0.046; P<0.05). The media TTP of the patients with low expression of ERCC1 mRNA is 6 months and the media TTP of the patients with high expression of ERCC1 mRNA is 5 months. The media OS of the patients with low expression of ERCC1 mRNA is 19 months and the media OS of the patients with high expression of ERCC1 mRNA is 17 months. By studying the correlations between ERCC1 mRNA expression and TTP/OS, statistical differences of TTP and OS are observed between the patients with low expression of ERCC1 mRNA and the patients with high exprssion of ERCC1 mRNA(P=0.026,0.011; P<0.05). There is statistical difference of response rate between low expression of TS mRNA, low expression of ERCC1 mRNA group and high expression of TS mRNA, high expression of ERCC1 mRNA group(X2=11.016, P=0.005; X2 >7.055,P<0.0083). TS gene comprises-6p/-6p,-6p/+6p and +6p/+6p. The median TTP of the-6p/-6p group is 8 months and the median TTP of the-6p/+6p and +6p/+6p group is 5 months. The median OS of the -6p/-6p group is 34 months and the median OS of the -6p/+6p and +6p/+6p group is 15 months. Statistical differences of TTP and OS are observed between the two groups(P<0.05). ERCC1 gene includes C/C, C/T and T/T. The median TTP of the C/C group is 6 months and the median TTP of the C/T and T/T group is 4 months. The median OS of the C/C group is 28 months and the median OS of the C/T and T/T group is 13 months. The differences of TTP and OS between the two groups are statistically significant(P <0.05). TS mRNA expression level and ERCC1 mRNA expression level are independent factors affecting the TTP of colorectal cancer patients. TS gene phenotype, ERCC1 genephenotype, TS mRNA expression level and ERCC1 mRNA expression level are independent factors affecting the OS of colorectal cancer patients.Conclusion:The patients with low expression of TS mRNA and the patients with low expression of ERCC1 mRNA could benefit from FOLFOX4 regimen. Detecting the polymorphisms of TS gene and ERCC1 gene plays a role in predicting the prognosis of patients with Ⅲ/Ⅳ colorectal cancers.