Lung cancer is the second most commonly diagnosed carcinoma and is the leading cause of cancer death. Although significant progress has been made towards its understanding and treatment, unraveling the complexities of lung cancer is still hampered by a lack of comprehensive knowledge on the mechanisms underlying the disease. High-throughput and multidimensional genomic data have shed new light on cancer biology. In this study, we developed a network-based approach integrating somatic mutations, the transcriptome, DNA methylation, and protein-DNA interactions to reveal the key regulators in lung adenocarcinoma (LUAD). By combining Bayesian network analysis with tissue-specific transcription factor (TF) and targeted gene interactions, we inferred 15 disease-related core regulatory networks in co-expression gene modules associated with LUAD. Through target gene set enrichment analysis, we identified a set of key TFs, including known cancer genes that potentially regulate the disease networks. These TFs were significantly enriched in multiple cancer-related pathways. Specifically, our results suggest that hepatitis viruses may contribute to lung carcinogenesis, highlighting the need for further investigations into the roles that viruses play in treating lung cancer. Additionally, 13 putative regulatory long non-coding RNAs (lncRNAs), including three that are known to be associated with lung cancer, and nine novel lncRNAs were revealed by our study. These lncRNAs and their target genes exhibited high interaction potentials and demonstrated significant expression correlations between normal lung and LUAD tissues. We further extended our study to include 16 solid-tissue tumor types and determined that the majority of these lncRNAs have putative regulatory roles in multiple cancers, with a few showing lung-cancer specific regulations. Our study provides a comprehensive investigation of transcription factor and lncRNA regulation in the context of LUAD regulatory networks and yields new insights into the regulatory mechanisms underlying LUAD. The novel key regulatory elements discovered by our research offer new targets for rational drug design and accompanying therapeutic strategies.
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