Abstract
BackgroundHead and neck squamous cell carcinoma (HNSCC) is a common cancer characterized by late diagnosis and poor prognosis. The aim of this study was to identify a novel ferroptosis-related DNA methylation signature as an alternative diagnosis index for patients with HNSCC.MethodsMethylome and transcriptome data of 499 HNSCC patients, including 275 oral squamous cell carcinoma (OSCC) samples, were obtained from The Cancer Genome Atlas (TCGA). An additional independent methylation dataset of 50 OSCC patients from the NCBI Gene Expression Omnibus (GEO) database was used for validation. As an index of ferroptosis activity, the ferroptosis score (FS) of each patient was inferred from the transcriptome data using single-sample gene set enrichment analysis. Univariate, multivariate, and LASSO Cox regression analyses were used to select CpG sites for the construction of a ferroptosis-related DNA methylation signature for diagnosis of patients.ResultsWe initially inferred the FS of each TCGA HNSCC patient and divided the samples into high- and low-FS subgroups. Results showed that the high-FS subgroup displayed poor overall survival. Moreover, 378 differentially methylated CpG sites (DMCs) were identified between the two HNSCC subgroups, with 16 selected to construct a 16-DNA methylation signature for risk prediction in HNSCC patients using the LASSO and multivariate Cox regression models. Relative operating characteristic (ROC) curve analysis showed great predictive efficiency for 1-, 3-, and 5-year HNSCC survival using the 16-DNA methylation signature. Its predictive efficiency was also observed in OSCC patients from the TCGA and GEO databases. In addition, we found that the signature was associated with the fractions of immune types in the tumor immune microenvironment (TIME), suggesting potential interactions between ferroptosis and TIME in HNSCC progression.ConclusionsWe established a novel ferroptosis-related 16-DNA methylation signature that could be applied as an alternative tool to predict prognosis outcome in patients with HNSCC, including OSCC.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is a common cancer characterized by late diagnosis and poor prognosis
Inferring ferroptosis score (FS) of HNSCC patients based on transcriptome data To assess ferroptosis activity in HNSCC, we collected ferroptosis-related genes from the FerrDb database [23]
We inferred the FSs of HNSCC patients as an index of ferroptosis activity based on the expression levels of the above two gene sets using single-sample gene set enrichment analysis (ssGSEA)
Summary
Head and neck squamous cell carcinoma (HNSCC) is a common cancer characterized by late diagnosis and poor prognosis. Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies worldwide and is associated with high morbidity and mortality [1]. According to the 2018 Global Cancer Report, there are 890,000 new HNSCC cases worldwide each year as well as 450,000 deaths [2]. The overall 5-year survival of HNSCC across all stages is ~ 60% [4, 5]. Despite considerable effort and advances in multimodal therapy, over 60% of patients diagnosed with HNSCC present at a locally advanced stage with a 5-year survival rate of less than 30% [6]. The identification of reliable prognostic biomarkers is urgently needed for early detection, effective treatment, and improved prognosis in HNSCC patients
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