Objective: Abnormal DNA methylation can regulate carcinogenesis in lung adenocarcinoma (LUAD), while transcription factors (TFs) mediate methylation in a site-specific manner to affect downstream transcriptional regulation and tumor progression. Therefore, this study aimed to explore the TF-methylation-gene regulatory relationships that influence LUAD prognosis.
Methods: Differential analyses of methylation sites and genes were generated by integrating transcriptome and methylome profiles from public databases. Through target gene identification, motif enrichment in the promoter region, and TF prediction, TF-methylation and methylation-gene relation pairs were obtained. Then, the prognostic TF-methylation-gene network was constructed using univariate Cox regression analysis. Prognostic models were constructed based on the key regulatory axes. Finally, Kaplan-Meier curves were created to evaluate the model efficacy and the relationship between candidate genes and prognosis.
Results: A total of 1878 differential expressed genes and 1233 differential methylation sites were screened between LUAD and normal samples. Then 10 TFs were predicted to bind 144 enriched motifs. After integrating TF-methylation and methylation-gene relations, a prognostic TF-methylation-gene network containing 4 TFs, 111 methylation sites, and 177 genes was constructed. In this network, ERG-cg27071152-MTURN and FOXM1-cg19212949-PTPR regulatory axes were selected to construct the prognostic models, which showed robust abilities in predicting 1-, 3-, and 5-year survival probabilities. Finally, ERG and MTURN were downregulated in LUAD samples, whereas FOXM1 and PTPR were upregulated. Their expression levels were related to LUAD prognosis.
Conclusion: ERG-cg27071152-MTURN and FOXM1-cg19212949-PTPR regulatory axes were proposed as potential biomarkers for predicting the prognosis of LUAD.
Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.