| ObjectiveGastric cancer(GC)ranks fifth in the incidence of malignant tumors in the world,and ranks fourth in the death rate of malignant tumors.It is extremely harmful to human health and is also a global health problem.Laurén classification,WHO classification system,AJCC classification system,TCGA and ACRG molecular classification play an important role in the clinical diagnosis,treatment and prognosis evaluation of gastric cancer patients,but the basis of these classifications is relatively single and not yet accurate Prediction of prognosis in patients with gastric cancer.New and effective biomarkers and more convenient and easy-to-implement typing methods are urgently needed clinically to better carry out molecular typing of gastric cancer patients,to select more accurate treatment methods for gastric cancer patients,and to prolong the survival time of patients.Improve the quality of life of patients.This study identifies the specific molecular characteristics of gastric cancer from the perspective of multi-omics,and constructs a multi-omics molecular classification of gastric cancer,which is of great significance for the clinical classification and treatment of gastric cancer.MethodsIn this study,we used multi-omics data from the TCGA-STAD cohort for clustering,including transcriptome RNA sequencing(m RNA expression,lnc RNA expression,mi RNA expression),DNA methylation,and somatic gene mutation data.We selected 243 patients with multi-omics characteristics and used the ’MOVICS’software package in R language to run 10 state-of-the-art clustering algorithms to identify patients with different molecular characteristics,and further validated in GSE62254,GSE26253,GSE15459 and GSE84437 external cohorts.Evaluate different activation signaling pathways across different subtypes using single-sample gene set enrichment analysis and compare differential distributions of gene mutations,gene copy number changes,and tumor mutational burden across different subtypes and perform immunohistochemistry via an external gastric cancer tissue microarray.The expression of the key factor SMOC2 and its relationship to prognosis were analyzed to assess prognostic differences between different subtypes and potential therapeutic response to immunotherapy and chemotherapy.ResultsIn this study,we classified gastric cancer patients into two molecular subtypes,CS1 and CS2,based on the analysis results of multi-omics and clustering algorithms,and compared the mean overall survival of CS1 subtype patients with CS2 subtype patients(28.5 vs.68.9 months,P = 0.016)and progression-free survival compared to the CS2 subtype(19.0 vs.63.9 months,P = 0.008)were significantly different.The CS1 subtype enhances activation of extracellular matrix-related pathways and the CS2 subtype enhances activation of cell cycle-related pathways.Furthermore,we screened SMOC2,a key factor,and found that the expression of SMOC2 in the CS1 subtype was4.537-fold higher than in the CS2 subtype.High expression correlates with tumor grade SMOC2 expression was positively correlated with vimentin protein,a marker of epithelial-mesenchymal transition(R = 0.3571).In the CS2 subtype,we observed significantly higher total mutations and more specific mutations in TTN,MUC16 and ARID1 A.Higher immune cell infiltration was also observed in the CS2 subtype,reflecting potential advantages of the CS2 subtype in immunotherapy.In addition,the CS2 subtype had a higher response rate to 5-fluorouracil,cisplatin,and paclitaxel than the CS1 subtype.Similar differences in clinical outcomes between CS1 and CS2 subtypes were successfully validated in external cohorts GSE62254,GSE26253,GSE15459,and GSE84437.ConclusionsIn this study,new insights into the molecular typing of gastric cancer were proposed through comprehensive analysis of multi-omics data and 10 multi-omics clustering algorithms for gastric cancer.Our study found that the expression of SMOC2 was significantly increased in the CS1 subtype,and the later the tumor stage,the higher the expression of SMOC2;the patients in the CS1 subtype had activation of EMTrelated signaling pathways,poor prognosis,and effective response to immunotherapy The CS2 subtype has a higher gene mutation rate,a higher level of activated immune cell infiltration,and a higher effective response rate to immunotherapy,which provides a new idea for the study of gastric cancer subtypes.Based on these specific molecular It is expected to provide a potential clinical therapeutic target for gastric cancer. |
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