Identification of a Necroptosis-Related Prognostic Signature and Associated Regulatory Axis in Lung Adenocarcinoma

BACKGROUND: Lung cancer is considered to be the second most aggressive and rapidly fatal cancer after breast cancer. Necroptosis, a novel discovered pattern of cell death, is mediated by Receptor-interacting serine/threonine-protein kinase 1 (RIPK1), Receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and Mixed Lineage Kinase Domain Like Pseudokinase (MLKL). METHODS: For the purpose of developing a prognostic model, Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was conducted. Using Pearson's correlation analysis, we evaluated the correlation between necroptosis-related markers and tumor immune infiltration. A bioinformatics analysis was conducted to construct a necroptosis-related regulatory axis. RESULTS: There was a downregulation of most of necroptosis-related genes in lung adenocarcinoma (LUAD) versus lung tissues but an increase in PGAM5, HMGB1, TRAF2, EZH2 levels. We also summarized the Single Nucleotide Variant (SNV) and copy number variation (CNV) of necroptosis-related genes in LUAD. Consensus clustering identified two clusters in LUAD with distinct immune cell infiltration and ESTIMATEScore. Genes related to necroptosis were associated with necroptosis, Tumor necrosis factor (TNF) signaling pathway, and apoptosis according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Four prognostic genes (ALDH2, HMGB1, NDRG2, TLR2) were combined to develop a prognostic gene signature for LUAD patients, which was highly accurate in predicting prognosis. Univariate and multivariate analysis identified HMGB1, pT stage, and pN stage as independent factors impacting on LUAD patients' prognosis. A significant correlation was found between the level of TLR2 and NDRG2 and clinical stage, immunity infiltration, and drug resistance. Additionally, the progression of LUAD might be regulated by lncRNA C5orf64/miR-582-5p/NDRG2/TLR2. CONCLUSION: The current bioinformatics analysis identified a necroptosis-related prognostic signature for LUAD and their relation to immunity infiltration. This result requires further investigation.