1.A Study On Molecular Characteristics Of Gastric Tumorigenesis 2.A Study On The Prediction Of Distant Metastatic Of Nasopharyngeal Carcinoma Based On T Cell Receptor Repertoire

Part One:A study on molecular characteristics of gastric tumorigenesis Chapter 1:Dissecting expression profiles of gastric precancerous lesions and early gastric cancer to explore crucial molecules in intestinal-type gastric tumorigenesisIntestinal-type gastric cancer(IGC)has a clear and multistep histological evolution.No studies have comprehensively explored gastric tumorigenesis from inflammation through low-grade intraepithelial neoplasia(LGIN)and high-grade intraepithelial neoplasia(HGIN)to early gastric cancer(EGC).We sought to investigate the characteristics participating in IGC tumorigenesis and identify related prognostic information within the process.RNA expression profiles of 94 gastroscopic biopsies from 47 patients,including gastric precancerous lesions(GPL:LGIN and HGIN).EGC and paired controls,were detected by Agilent Microarray.We observed that LGIN and HGIN had similar expression profiles when compared to EGC,HGIN showed a potentially invasive feature when compared to LGIN and the immune microenvironment was more active in EGC than in GPL.During IGC tumorigenesis from LGIN through HGIN to EGC,the number of activity-changed tumor hallmarks increased and we observed an increase in the stemness of gastric epithelial cells in LGIN,HGIN and EGC.There were many gene signatures that were significantly related to the overall and disease-free survival of gastric cancer patients in IGC tumorigenesis.These gene signatures had a significantly higher prognostic efficacy than the established gene signatures.In addition,we found that GSTM2 was persistent low expression and persistently differential co-expression during IGC tumorigenesis,it was related to the drug resistance of gastric cancer patients.In conclusion,during IGC tumorigenesis,cancer-like changes occur in LGIN and accumulate in HGIN and EGC.HGIN obtains the potential invasive feature relative to LGIN.The immune microenvironment is more active in EGC than in LGIN and HGIN.The identified signatures from the tumorigenesis process have robust prognostic significance for GC patients.Chapter 2:Multi-omics sequencing of time-progressing intestinal gastric precancerous lesions and gastric cancer tissuesThe genomic abnormal molecular events in gastric cancer have been largely catalogued,however,the order of their occurrence is not known.Gastric cancer is known to be a heterogeneous disease.We enrolled two patients with gastric disease,for each patient,the relatively normal gastric mucosal tissue,LGIN,HGIN and gastric cancer tissue that were collected at different time points and leukocytes were sequenced in multi-omics including whole genome sequencing,whole exome sequencing and transcriptome sequencing.We observed that there were a certain amount of gene mutations,copy number variations and gene fusions in normal gastric mucosa,but there no driver gene mutations,and driver gene mutations appeared in precancerous lesions.The abnormal molecular events in precancerous lesions were similar to those in gastric cancer.In the process of gastric tumorigenesis,the copy number variations might occur before the gene mutations.In addition,we also detected a high-frequency mutant gene SVEP1 that might play a critical role in gastric tumorigenesis.Part Two:A study on the prediction of distant metastatic of nasopharyngeal carcinoma based on T cell receptor repertoireTo date,there are no peripheral blood biomarkers that were suitable for all nasopharyngeal carcinoma(NPC)patients to predict distant metastasis.Peripheral blood T-cell receptor(TCR)repertoire has been reported showing prognostic prediction in a variety of cancers.We detected the TCR repertoire of pre-and post-treatment blood samples from NPC patients with non-metastasis(nM,n=21)or with distant metastasis after treatment(M,n=19)by high-throughput sequencing.We compared the dynamics of TCR repertoire between nM and M groups and investigated the distant metastatic predicting value of TCR repertoire in NPC patients.In both nM and M groups,the cumulative frequency of top10%and top 100 clones were significantly increased,the richness and evenness were significantly decreased after treatment.However,whether in the entire TCR repertoire or in the overlap clones,the increase in the proportion of large clones was significantly higher in nM than in M group.The TCR diversity was significantly decreased in M group after treatment,but not in nM group.More importantly,the ascending TCR diversity(p=0.036)and higher similarity between pre-and post-treatment samples(p=0.014)showed better distant metastatic-free survival(DMFS).The similarity still had robust DMFS prediction in patients with reduced TCR diversity.In conclusion,treatment had different effects on the composition of TCR repertoire between patients with non-metastasis and patients with distant metastasis after treatment.The dynamic of TCR diversity and similarity of TCR repertoire could serve as noninvasive DMFS predictors for all NPC patients.