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Epigenetic Scanning of CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas. | LitMetric
Background : The KEAP1/NRF2 (Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2) pathway modulates detoxification processes and participates in the resistance of solid tumors to therapy. Scientific evidence about the presence of genetic and epigenetic abnormalities of the gene was firstly reported in non-small-cell lung cancer (NSCLC) and then described in other tumors. At present, the prognostic role of aberrant methylation at cytosine-guanine dinucleotide (CpG) sites of the gene promoter is debated in NSCLC, and its correlation with transcriptional changes and protein levels remains to be defined in large sample cohorts.Methods : We evaluated and compared multiple KEAP1 omics data (methylation, transcript, and protein expression levels) from The Cancer Genome Atlas (TCGA) to explore the role of CpGs located in different portions of and the correlation between methylation, transcription, and protein levels. Data from two subsets of lung adenocarcinoma (LUAD, = 617) and lung squamous cell carcinoma (LUSC, = 571) cohorts of NSCLC patients with different disease stages were evaluated.Results : We found that the methylation levels of many CpGs at various promoter and intragenic locations showed a significant inverse correlation with the transcript levels. Interestingly, these results were limited to the wild-type LUSC and LUAD cohorts, whereas in LUAD the effect of the epigenetic silencing of on its transcription was also observed in the mutated subpopulation.Conclusions : These results support the idea that the prognostic role of CpG sites warrants more in-depth investigation and that the impact of their changes in methylation levels may differ among specific NSCLC histologies and molecular backgrounds. Moreover, the observed impact of epigenetic silencing on expression in specific and settings may suggest a potential role of methylation as a predictive marker for NSCLC patients for whom anti-EGFR treatments are considered.
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