Identification And Integrated Analysis Of Key Genes In Association With Development And Progression Of Adenocarcinoma At The Gastroesophageal Junction In Chinese Population

Objective:This study aims to explore the genomic and transcriptomic changes of adenocarcinoma at the gastroesophageal junction(ACGEJ)in the Chinese population and identify key genes in the occurrence and progression of this cancer.Methods:We collected ACGEJ tumors,adjacent non-tumor tissues,and peripheral blood samples from 58 patients who were recruited at the Linzhou Cancer Hospital and Linzhou Esophageal Cancer Hospital.The collected samples were analyzed by whole-exome sequencing(WES)and RNA sequencing.We used the dN/dS method to search for mutations under positive selection in ACGEJ as candidate driver mutations.The gene expression level of ACGEJ tumor and paired non-tumor samples were compared to identify dysregulated genes by limma.The enriched pathways of these genes were analyzed by using gene set variation analysis(GSVA).To identify key genes in the progression of ACGEJ,we tested the association between the expression of dysregulated genes and the prognosis of ACGEJ patients by using the LASSO regression model.Based on the multivariate Cox regression analysis,the clinical features and prognosis associated gene set were applied to establish the Nomogram model.The Nomogram prognostic value was tested by using c-index and calibration.Results:Through genomic analyses,we found 4018 somatic mutations in 55 ACGEJ tumor samples and discovered 11 driver genes,including TP53,ARID1A,SMAD4,PIK3CA,MUC6,KRAS,PTEN,CDKN2A,MAP2K7,RNF43 and RHOA.Among these genes,the MAP2K7,RNF43 and RHOA were identified as novel driver genes in ACGEJ.Through transcriptomic profiling of tumor and non-tumor ACGEJ samples,we identified 558 significantly up-regulated and 179 down-regulated differentially expression genes(DEGs)in ACGEJ(|log2FC|>1.2,P<0.05).The DEGs were enriched in the pathways related to tumor proliferation,growth,metastasis and metabolism.Among these DEGs,a total of 9 genes(ASF1B,ACTN1,KNL1,SAPCD2,TP53111,DMBT1,CNFN,ID2,DPT)were identified to associate with the prognosis of ACGEJ patients by LASSO regression model.These 9 genes were further selected to build a prognostic model.The patients could be divided into two groups by this prognostic model,and the overall survival(OS)of ACGEJ patients in the two groups was significantly different(P=0.0013).A nomogram was established which included the age,clinical stage and prognosis associated gene set for eventual clinical translation(c-index=0.81).Conclusions:We performed an integrated analysis of exome and transcriptome to identify the key genes associated with the occurrence and progression of ACGEJ.The identified genes may be potential treatment targets and prognostic biomarkers of this disease.