Study Of Gene Expression Profiles And Oncogenic Signaling Pathways Alteration Landscape In Stage IA Non-Small Cell Lung Cancer

BackgroundLung cancer is the leading cause of cancer-related mortality in the world.Non-small cell lung cancer is the most common variety accounting for nearly 85%of the cases.Targeted therapies could provide sustaining clinical benefits for patients who carry sensitive mutations,even with less adverse effects comparing with chemotherapies.Great progress in the field of targeted therapies has been made in advanced lung cancer,but not in early-stage NSCLC.And research of gene and pathway alteration analysis in stage IA NSCLC is much less.ObjectiveTo elucidate the gene expression profiles and mutation landscape,and oncogenic signaling pathways alteration landscape in stage IA NSCLC.Methods1.Download the mRNAseq and clinical data of stage IA NSCLC from TCGA database.Gene expression analysis based on these data can quickly detect the differentially expressed genes(DEGs)using DESeq algorithm.Then GO term analysis and biological pathway enrichment analysis of selected DEGs were performed using the DAVID database.2.By reviewing and compiling the published scientific literatures about oncogenic signaling pathways and pathway databases(including KEGG and REACTOME),we finally evaluated several canonical oncogenic signaling pathways and key genes explored in these pathways.Then we performed pathway alteration analysis in stage IA NSCLC,and elucidated the probable associations between pathway alteration frequencies and clinical pathologic parameters.3.Collect the clinical and gene detecting data of stage IA NSCLC in our hospital from Jan 2016 to Dec 2019,and perform alteration analysis of the main driver genes in lung cancer.Results1.Based on TCGA database,from the GO term analysis of the selected DEGs in stage IA NSCLC,we found that adenocarcinoma is greatly associated with immune response in the three functional groups:cellular component,molecular function and biological process,while squamous carcinoma is mainly associated with the function of epithelium.The biological pathway enrichment analysis through KEGG shows that there are overlaps of enriched pathways in adenocarcinoma and squamous carcinoma,and meanwhile both of them have their own specific enriched pathways.2.Based on bioinformatics analysis,we found that the alteration frequencies of common driver genes in stage IA NSCLC are nearly consistent with that in NSCLC containing all stages,expect for KRAS and EGFR,which are lower in stage IA.The RTK/RAS and p53 signaling pathways have the highest alteration frequencies in stage IA NSCLC,where RTK/RAS mainly in adenocarcinoma and p53 mainly in squamous carcinoma.Particularly,the alteration frequency of TGF β pathway is very low in stage IA NSCLC.3.The real-world study shows that the most common mutations of EGFR are the small in-frame deletions in exon 19(19DEL)and a substitution mutation,L858R in exon 21,nearly accounting for 85%in all mutations.The others are rare mutations and compound mutations.For KRAS,the mutation frequency in codon 12 is very high,mainly in G12C,G12V and G12D.The alterations in ERBB2 are mostly insertions in exon 20,and then the amplifications of ERBB2 follows.Conclusion1.In stage IA NSCLC,gene alterations in adenocarcinoma are greatly associated with immune response,while in squamous carcinoma are mainly associated with the functions of epithelium.2.The oncogenesis of adenocarcinoma in stage IA is closely associated with the dysregulation of RTK/RAS signaling pathway,while squamous carcinoma mainly with dysregulations of p53 pathway.3.In stage IA NSCLC,the major mutations of EGFR are 21 L858R and 19DEL,and ERBB2 is mostly 20 ins,while KRAS mainly mutates in codon 12.To a certain extent,it provides evidence for the options of adjuvant targeted therapies for patients of stage IA NSCLC.