High expression of LAMA3/AC245041.2 gene pair associated with KRAS mutation and poor survival in pancreatic adenocarcinoma: a comprehensive TCGA analysis

Abstract

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is one of the most challenging cancers with high morbidity and mortality. KRAS mutations could occur as an early event in PAAD. The present study aimed to identify the differentially expressed lncRNAs (DE-lncRNAs) and differentially expressed mRNAs (DE-mRNAs) in KRAS-mutant PAAD to explore the pathogenesis and the underlying molecular mechanism of PAAD development. METHODS: Clinical data of TCGA-PAAD patients were downloaded from the TCGA database and subjected to survival analysis along with the KRAS mutation information data. Weighted gene correlation network analysis (WGCNA) and univariate Cox regression analysis were conducted to construct prognostic risk models to identify the hub DE-mRNAs and DE-lncRNAs associated with PAAD prognosis. GO and KEGG enrichment analyses of the identified hub DE-mRNAs were performed. Multivariate cox regression analysis was performed to analyze the overall prognosis of age, gender, pathologic_T, and KRAS mutations, following which the differences in the clinical characteristics of risk score1 and risk score2 were analyzed. Finally, the mRNAs-lncRNA-TFs regulatory network was constructed. RESULTS: Functional enrichment analysis was performed after screening 1671 DE-mRNAs and 324 DE-lncRNAs. It was observed that the associated pathways were enriched mainly in the modulation of chemical synaptic transmission, synaptic membrane, ion-gated channel activity, ligand-receptor interactions that stimulate neural tissue, among others. The univariate Cox regression analysis screened 117 mRNAs and 36 lncRNAs, and the risk ratio models of the mRNAs and lncRNAs were constructed. LAMA3 (mRNA) and AC245041.2 (lncRNA) exhibited a strong expression correlation in the respective two risk models. The genes in the samples with a high expression of these two genes were enriched in several pathways associated with transcription factors (TFs), among which the TFs ATF5, CSHL1, NR1I2, SIPA1, HOXC13, HSF2, and HOXA10 were shared by the two groups. The core enrichment genes in the common TF pathways were collated, and the mRNAs-lncRNAs-TFs regulatory network was constructed. CONCLUSION: In the present study, novel prognostic mRNAs and lncRNAs were identified, and their respective prognostic models and nomograms were constructed to guide clinical practice. An mRNAs-lncRNAs-TFs regulatory network was also constructed, which could assist further research in the future.