The Study Of Metabonomics And DNA Methylation Markers In The Diagnosis And Prediction Of Adverse Effects Of Capecitabine In Colorectal Cancer

Colorectal cancer(CRC)is one of the most common gastrointestinal cancer in the world and has gets a lot of attention.In recent years,the incidence and the 5 year survival rate of CRC have declined with the changes of habits and customs,and universalize of colonoscopy.However,the incidence and mortality in China are still high.This is mainly due to the early colorectal cancer is often asymptomatic,and most of the patients are often in the middle or late stages when diagnosed.Therefore,the study of biomarkers for early diagnosis of CRC and prediction of adverse effects(AEs)for chemotherapy has become hot spots in recent years.The main purpose of this study is to screen the metabolic and DNA methylation markers for the diagnosis of CRC and the prediction of adverse effects for capecitabine.Metabolomics of urine is detected by Ultra Performance Liquid Chromatography-Quadrupole-Time of Flight Mass Spectrometric Analysis.The methylation level of tumor tissues and normal tissues is detected by Illumina Human Methylation 850 K Bead Chip.In this way,screen the potential biomarkers for early diagnosis and adverse effects for capecitabine preliminary.Part 1.The value of tumor markers and inflammatory markers for diagnosis and prediction of adverse effects of capecitabine in colorectal cancerObjective:1.To explore the value of combined detection of preoperative tumor markers for the diagnosis of CRC,as well as the role of these markers and inflammatory markers for predicting adjuvant-chemotherapy-related AEs.2.To observe the frequency and severity of adverse reactions of capecitabine chemotherapy in colorectal cancer patients in our hospital.Methods:The datas included 952 cases from retrospective study and 260 from prospective study in Shanghai Changzheng Hospital,and 617 cases from TCGA database.Statistical analyses were carried out to examine the associations between preoperative tumor markers,inflammatory markers and diagnose of CRC,as well as adjuvant-chemotherapy-related AEs.Results:1.The false negative rate(FNR)of CEA,CA19-9 and CA125 were mainly affected by pathological stages.2.The combined detection of CEA,CA19-9,CA125 and fecal occult blood can improve the diagnostic sensitivity of CRC and reduce the FNR.However,the FNR of combined screening is still high,and there is an urgent need for marker system with high accuracy and diagnostic value.3.Preoperative platelet-lymphocyte ratio(PLR)has the potential to predict hand foot syndrome.Preoperative blood cell has the potential to predict myelosuppression.The low predictive value requires sensitive and highly specific biomarkers for predicting AEs.Part 2.The study of metabonomics biomarkers for the diagnosis and prediction of AEs of capecitabine in CRCObjective:Screen the metabolic markers for the diagnosis of colorectal cancer and prediction of AEs of capecitabine.Methods:UHPLC-Q-TOF-MS was used to detect nontarget endogenous metabolites in urine.The value of endogenous metabolites in the diagnosis of colorectal cancer and the prediction of AEs of capecitabine were analyzed.Results:1.There are differences in the metabolomics of urien between the CRC and the normal people,and the metabonomics can be used as one of the directions for the exploration of the potential markers.2.The endogenous metabolites N1,N12-Diacetylspermine,3-methylhistidine,Hippuric acid,3-Hydroxyhippuric acid can be used as potential biomarkers for the diagnosis of colorectal cancer.The FNR rate of the 4 combined diagnostic equations is far lower than the combination screening of serum tumor markers and fecal occult blood.3.N1,N12-Diacetylspermine,4-pyridoxic acid,and L-carnitine have potential values in predicting hand foot syndrome.4-pyridoxic acid,L-carnitine and 2-Octenoylcarnitine have potential values in predicting myelosuppression.The predictive value is weak.Sensitive and highly specific biomarkers are needed for predicting AE(s).Part 3.The study of DNA methylation as biomarkers for the diagnosis and prediction of AEs of capecitabine in CRCObjective:Screen the DNA methylation biomarkers for the diagnosis and prediction of AE(s)of capecitabine in colorectal cancer.Methods:The methylation level of colorectal cancer tissues and normal tissues was detected by human 850 k Illumina(850K).The potential DNA methylation biomarkers in predicting AEs of capecitabine and studying the occurrence of CRC were screened by bioinformatics.Results:1.Cg18856388 and cg16059038 were new methylation sites associated with CRC,which haven't been reported previously and have the value of studying the occurrence of CRC.2,20 potential sites for the study of CRC and the diagnosis of CRC were screened.Their value of distinguishing the CRC tumor tissue and normal tissue was slightly higher than that of the previously reported sites,which could be used as a potential marker for the diagnosis of CRC.3.Several potential biomarkers for predicting the AEs of capecitabine in colorectal cancer were screened.Its predictive efficacy,gene function and associated network still need further analysis and excavation.