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Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell
Federico Pio Fabrizio1, Tommaso Mazza2, Stefano Castellana2
1Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy.
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 KEAP1 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 KEAP1 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 KEAP1 and the correlation between methylation, transcription, and protein levels. Data from two subsets of lung adenocarcinoma (LUAD, n = 617) and lung squamous cell carcinoma (LUSC, n = 571) cohorts of NSCLC patients with different disease stages were evaluated.
Results:
We found that the methylation levels of many KEAP1 CpGs at various promoter and intragenic locations showed a significant inverse correlation with the transcript levels. Interestingly, these results were limited to the KRAS wild-type LUSC and LUAD cohorts, whereas in LUAD the effect of the epigenetic silencing of KEAP1 on its transcription was also observed in the EGFR mutated subpopulation.
Conclusions:
These results support the idea that the prognostic role of KEAP1 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 KEAP1 expression in specific KRAS and EGFR settings may suggest a potential role of KEAP1 methylation as a predictive marker for NSCLC patients for whom anti-EGFR treatments are considered.
Insights
Aberrant methylation of KEAP1 (Kelch-like ECH-associated protein 1) CpG sites inversely correlates with its transcript levels in non-small-cell lung cancer (NSCLC). This epigenetic silencing may serve as a predictive marker for targeted therapies in specific NSCLC subtypes.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- The KEAP1/NRF2 pathway is crucial for detoxification and tumor therapy resistance.
- KEAP1 gene abnormalities are observed in various cancers, including non-small-cell lung cancer (NSCLC).
- The prognostic significance of KEAP1 promoter methylation in NSCLC and its correlation with gene expression remain unclear.
Purpose of the Study:
- To investigate the role of KEAP1 CpG sites across different genomic locations.
- To analyze the correlation between KEAP1 methylation, transcript, and protein levels.
- To explore the impact of KEAP1 epigenetic alterations in specific NSCLC molecular subtypes.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) database for KEAP1 omics data (methylation, transcript, protein).
- Analyzed methylation, transcript, and protein expression in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) cohorts.
- Correlated KEAP1 CpG methylation with transcript levels in KRAS wild-type and EGFR-mutated NSCLC.
Main Results:
- Significant inverse correlation observed between KEAP1 CpG methylation and transcript levels across various promoter and intragenic sites.
- This correlation was primarily noted in KRAS wild-type LUAD and LUSC.
- Epigenetic silencing of KEAP1 also impacted its transcription in EGFR-mutated LUAD.
Conclusions:
- KEAP1 CpG site methylation warrants further investigation for prognostic value in NSCLC.
- The impact of KEAP1 methylation varies with NSCLC histology and molecular background.
- KEAP1 methylation may serve as a predictive biomarker for anti-EGFR therapy in specific NSCLC patient groups.
