Association Study Between Single Nucleotide Polymorphisms In Folic Acid Metabolism Pathway And Effect Of First-line Chemotherapy And Prognosis For Metastatic Colorectal Cancer

Colorectal cancer(CRC)is one of the most common gastrointestinal malignancy.The prognosis of different stage has obvious difference,and 5-year survival rate for advanced metastatic colorectal cancer(mCRC)patients is only about 13%,which made serious threat to human health.Different mCRC patients even accept the same first-line chemotherapy,the curative effect and prognosis between different individuals varies significantly,and such difference can not entirely explained by factors such as age,gender or chemotherapy doses.It is still a question on how to predict individually the curative effect of first-line chemotherapy and prognosis,and there is no consensus now.5-FU(fluorouracil)is the cornerstone drug of the first-line chemotherapy for mCRC,and its main mechanism in anti-tumor is to inhibit normal function of TS(thymidylate synthetase)to syntheesis dTMP(deoxythymidine monophosphate).FdUMP(5-fluoro deoxyuridine acid phosphate)is the metabolite of 5-FU,and it has a cofactor called 5,10-CH2FH4(5,10-methylenetetrahydrofolate folinic acid).FdUMP can combine together with TS with the help of 5,10-CH2FH4 to form a ternary complex,there inhibit normal function of TS.But the content of 5,10-CH2FH4 under the condition of physiological is less,and the complex is often not stable and easy to disintegrate.CF(calcium folinate)is commonly used as sensitization agent of 5-FU.CF can metabolize to 5,10-CH2FH4 in the body via several key enzymes in the folate metabolism pathway,and therefore amplify the cytotoxic effect of 5-FU.From what has been discussed above,folic acid metabolic pathway has a potentially important role in first-line chemotherapy for mCRC patients.Genetic background is a key factor of curative effect of first-line chemotherapy and prognosis for mCRC,and SNP(single nucleotide polymorphism)is one of the most widely researched genetic genomics markers.The association between SNP of single gene in folic acid metabolism pathway and curative effect and prognosis of mCRC have been researched widely,but the conclusions are not unified.This study systematically for the first time to bring into all key genes SNPs in the folate metabolism pathways,and screen and analyze the markers that influence effect of first-line chemotherapy and prognosis for mCRC patients.By analyzing prognostic markers and other information,several studies establish the prediction model for the prognosis of malignant patients.Due to the cost and accuracy of the model,the results of the study is not easy to promote in the clinical.In recent years,the nomogram was widely noted because the good interface experience that it can provide and its ability to accurately predict individual prognosis,and the related research have been published on multiple top magazines.Based on the analysis of data including SNPs in folic acid metabolic pathways,clinical,pathological and follow-up information,this study for the first time to tentatively set up a nomogram model to predict the PFS probability of the mCRC patients.This study will discuss from the following two parts:Part ?:Association analyses between single nucleotide polymorphisms in folic acid metabolism pathway and effect of first-line chemotherapy and prognosis for metastatic colorectal cancerPurpose:To find the association between SNPs in folic acid metabolic pathways and effect of first-line chemotherapy and prognosis for mCRC patients.Methods:This is a retrospective study,and a total of 304 mCRC patients are included.Potential 17 SNPs were selected using bioinformatics methods,and genotyping were performed by the TaqMan method.The association between SNPs in folic acid metabolism pathway and curative effect of first-line chemotherapy and prognosis for mCRC patients were analyzed using SAS software,with the general epidemiological,clinical,pathological and follow-up information being taken into consideration.Results:The ALDH1L2 rs12582090(P<0.01)affect the DCR(diseases control rate)for mCRC patients that received first-line chemotherapy;FTCD rs10432965(P<0.01)and rs61729391(P=0.04)affect the PFS(progress free survival)of the mCRC;AMT rs4987107(P=0.01),DHFRL1 rs17855824(P=0.04)and RFC1 rs1057807(P=0.02)are associated with OS(overall survival).Conclusion:SNPs in folic acid metabolism pathway are significantly associated with the effect of first-line chemotherapy and prognosis for mCRC patients.Part ?:A nomogram model based on single nucleotide polymorphisms in folic acid metabolism pathway to predict PFS for metastatic colorectal cancer patientsPurpose:To build a nomogram model based on SNPs in folic acid metabolism pathway in predicting PFS of mCRC patients.Methods:On the basis of results of the first part,potentially relevant variables including SNPs were assigned into the program.Program were run by R software,and nomogram model in predicting one-year and three-year PFS of mCRC is set up.Results:A nomogram was successfully established with a Harrell's CI(concordance index)=0.56(95%CI=0.60-0.52).Conclusion:With the use of a nomogram model,PFS of the mCRC treated with first-line chemotherapy can be predicted,and the probability can be acquired accurately and intuitively,which has a certain guiding value.