Abstract
Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell lung cancer (NSCLC). LUSC occurs at the bronchi, shows a squamous appearance, and often occurs in smokers. To determine the epigenetic regulatory mechanisms of tumorigenesis, we performed a genome-wide analysis of DNA methylation in tumor and adjacent normal tissues from LUSC patients. With the Infinium Methylation EPIC Array, > 850,000 CpG sites, including ~350,000 CpG sites for enhancer regions, were profiled, and the differentially methylated regions (DMRs) overlapping promoters (pDMRs) and enhancers (eDMRs) between tumor and normal tissues were identified. Dimension reduction based on DMR profiles revealed that eDMRs alone and not pDMRs alone can differentiate tumors from normal tissues with the equivalent performance of total DMRs. We observed a stronger negative correlation of LUSC-specific gene expression with methylation for enhancers than promoters. Target genes of eDMRs rather than pDMRs were found to be enriched for tumor-associated genes and pathways. Furthermore, DMR methylation associated with immune infiltration was more frequently observed among enhancers than promoters. Our results suggest that methylation of enhancer regions rather than promoters play more important roles in epigenetic regulation of tumorigenesis and immune infiltration in LUSC.
Highlights
IntroductionLung squamous cell carcinoma (LUSC) is a subtype accounting for 20~30% of total cases of non-small-cell lung cancer (NSCLC)
Lung squamous cell carcinoma (LUSC) is a subtype accounting for 20~30% of total cases of non-small-cell lung cancer (NSCLC).LUSC occurs at the bronchi, shows a squamous appearance, and often leads to keratinization[1]
Using the Infinium Methylation EPIC Array, we profiled the methylation status of > 850,000 CpG sites for tumors and adjacent normal tissues obtained from 37 LUSC patients
Summary
Lung squamous cell carcinoma (LUSC) is a subtype accounting for 20~30% of total cases of non-small-cell lung cancer (NSCLC). LUSC occurs at the bronchi, shows a squamous appearance, and often leads to keratinization[1]. LUSC often occurs in smokers; several studies have demonstrated an association between smoking and LUSC2,3. The identification of oncogenic driver alterations and their matched targeted therapies are largely limited to the other major subtype of NSCLC, adenocarcinoma[4]. LUSC patients respond to immune checkpoint blockade, partly owing to their relatively high mutation burden. Many clinical trials on immune checkpoint blockade have been undertaken for LUSC patients[5]. The fibroblast growth factor receptor (FGFR), insulin-like growth factor (IGF), and PI3-AKT signaling pathways have been examined as new targeted therapies[4]
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