Lung cancer is the most common and fatal malignant tumour worldwide with a five‐year overall survival rate of only 15%. Lung adenocarcinoma (LUAD) is a heterogeneous disease. The use of microarray datasets along with bioinformatics knowledge might help to clarify the expression profile of cancer, molecular markers for the initial screening of tumour and the underlying biological mechanisms. The present study is designed to identify differential expression genes and molecular mechanisms of LUAD compared to normal lung tissues using systems biology approaches.
Methods Four GSE datasets (GSE75037, GSE63459, GSE32863 and GSE10072) were selected from the Gene Expression Omnibus (GEO) database. Data processing and meta-analysis were performed using the R statistical programming language, The differentially expressed genes (DEGs) associated with each stage were obtained. The common and unique DEGs between stages of LUAD and adjacent normal lung tissues were initiated by Venny tool. Common genes, including upregulated and downregulated genes, were then analyzed to a STRING database to obtain protein-protein interaction (PPI). STRING output was analyzed by MCODE and CytoHubba applications of Cytoscape to identify modules of co-expression and hub genes, respectively.
Results The shared upregulated and downregulated DEGs among LUAD stages were 22 and 140 genes, respectively, when compared to normal lung tissues. Unique genes for each stage were also identified. The hub genes were PECAM1, TEK, CDH5, VWF and ANGPT1. Most of the top cluster genes were enriched for Gα(s) signalling events, GPCR ligand binding, class B/2 (Secretin family receptors), platelet activation, signalling and aggregation in the main three co-expression clusters. Most of the shared genes (16 genes) were enriched in the metabolic pathway of hemostasis. Meaningful signaling pathways for unique genes were found at each stage.
Conclusions In the present study main three co-expression clusters, metabolic pathways and biological processes were identified to understand mechanisms underlying LUAD pathogenesis, development and progression at different stages. Unique upregulated and downregulated DEGs at each stage were identified with FERMT1 and SIX1 as specific early-stage diagnostic biomarkers for stage IB and IIB. 5 hub genes were observed, including PECAM1, TEK, CDH5, vWF and ANGPT1 which might be crucial for the onset and progression of LUAD.