Abstract
Background: Epigenetic alterations, such as DNA methylation patterns, yield an important role in the initiation, progression and prognosis of laryngeal squamous cell carcinoma (LSCC). We performed a genome-wide integrated analysis of methylation and the transcriptome to establish epigenetic signature to improve the accuracy of survival prediction and optimize therapeutic strategies for LSCC.Methods: LSCC DNA methylation datasets and RNA sequencing (RNA-seq) datasets were acquired from the Cancer Genome Atlas (TCGA). MethylMix was applied to detect DNA methylation-driven genes (MDGs). By univariate and multivariate Cox regression analyses, five genes of DNA MDGs was developed an epigenetic signature. The predictive accuracy and clinical value of the epigenetic signature were evaluated by receiver operating characteristic (ROC) and decision curve analysis (DCA), and compared with TNM stage system. Additionally, prognostic value of the epigenetic signature was validated by external Gene Expression Omnibus (GEO) database. According to 5 MDGs of epigenetic signature, the candidate small molecules for LSCC were screen out by the CMap database.Results: A total of 88 DNA MDGs were identified, five of which (MAGEB2, SUSD1, ZNF382, ZNF418 and ZNF732) were chosen to construct an epigenetic signature. The epigenetic signature can effectively divide patients into high-risk and low-risk group, with the area under curve (AUC) of 0.8 (5-year OS) and AUC of 0.745 (3-year OS). Stratification analysis affirmed that the epigenetic signature was still a significant statistical prognostic model in subsets of patients with different clinical variables. Multivariate Cox regression analysis indicated the efficacy of epigenetic signature appears independent of other clinicopathological characteristics. In terms of predictive capacity and clinical usefulness, the epigenetic signature was superior to traditional TNM stage. Additionally, the epigenetic signature was confirmed in external LSCC cohorts from GEO. Finally, CMap matched the 10 most significant small molecules as promising therapeutic drugs to reverse the LSCC gene expression.Conclusion: An epigenetic signature, with five DNA MDGs, was identified and validated in LSCC patients by integrating multidimensional genomic data. Compared TNM stage alone, it generates more accurate estimations of the survival probability and maybe offer novel research directions and prospects for individualized treatment of patients with LSCC.
Pyrosequencing-based DNA methylation profiling of Fanconi anemia/BRCA pathway genes in laryngeal squamous cell carcinoma