Integrated data analysis reveals significant associations of KEAP1 mutations with DNA methylation alterations in lung adenocarcinomas

Abstract

<i>KEAP1</i> regulates the cytoprotection induced by NRF2 and has been reported to be a candidate tumor suppressor. Recent evidence has shown that mutations in several driver genes cause aberrant DNA methylation patterns, a hallmark of cancer. However, the correlation between <i>KEAP1</i> mutations and DNA methylation in lung cancer has still not been investigated. In this study, we systematically carried out an integrated multi-omics analysis to explore the correlation between <i>KEAP1</i> mutations and DNA methylation and its effect on gene expression in lung adenocarcinoma (LUAD). We found that most of the DNA aberrations associated with <i>KEAP1</i> mutations in LAUD were hypomethylation. Surprisingly, we found several NRF2-regulated genes among the genes that showed differential DNA methylation. Moreover, we identified an 8-gene signature with altered DNA methylation pattern and elevated gene expression levels in LUAD patients with mutated <i>KEAP1</i>, and evaluated the prognostic value of this signature in various clinical datasets. These results establish that <i>KEAP1</i> mutations are associated with DNA methylation changes capable of shaping regulatory network functions. Combining both epigenomic and transcriptomic changes along with <i>KEAP1</i> mutations may provide a better understanding of the molecular mechanisms associated with the progression of lung cancer and may help to provide better therapeutic approaches.