Abstract
Genetic alteration involving N6-methyladenosine (m6A) regulatory genes is a frequent characteristic of multiple tumors. Nevertheless, little is known regarding their genetic alteration signatures and prognostic values in head and neck squamous cell carcinoma (HNSCC). In this study, RNA sequence profiles and copy number variation (CNV) data of 506 HNSCC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Correlation analysis involving alteration of m6A regulatory genes, clinicopathological characteristics, and patient survival was performed using R language. The results suggest that alteration of m6A regulatory genes was correlated with clinical staging. Patients with high expression of ALKBH5, FTO, METTL14, WTAP, YTHDC1, YTHDF1, and YTHDF2 had poor overall survival (OS) than those with low expression. Univariate and multivariate Cox regression analyses showed that ALKBH5 and YTHDC2 were independent risk factors for OS. However, patients with high YTHDC2 expression had better OS. Moreover, according to machine learning results, YTHDC2 was found to be the most important gene among the 10 m6A regulators. Additionally, high expression of YTHDC2 was correlated with activation of apoptosis and ubiquitin-mediated proteolysis. Here, we identified alterations to m6A regulatory genes in HNSCC for the first time and found that seven m6A regulators were associated with poor prognosis, especially ALKBH5, whereas YTHDC2 was associated with better prognosis. These m6A-related regulators could act as novel prognostic biomarkers for HNSCC. Our findings provide clues for understanding RNA epigenetic modifications in HNSCC.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is a common clinically malignant tumor that mainly occurs on the mucous surface of the upper respiratory digestive tract, such as the nasal cavity, paranasal sinuses, nasopharynx, hypopharynx, larynx, trachea, oral cavity, and oropharynx
The deletion of m6A methyltransferase METTL3 leads to selective splicing and gene expression alteration of >20 genes involved in the TP53 signaling pathway in hepatocellular carcinoma (HCC) [14]
It was found that the 10 m6A regulatory genes had different levels of copy number variation (CNV) events though analysis using GISTIC, ranging from 23.58 to 57.36%
Summary
Head and neck squamous cell carcinoma (HNSCC) is a common clinically malignant tumor that mainly occurs on the mucous surface of the upper respiratory digestive tract, such as the nasal cavity, paranasal sinuses, nasopharynx, hypopharynx, larynx, trachea, oral cavity, and oropharynx. In order to improve outcomes in HNSCC cases, identifying molecular genetic events during tumor progression is crucial to understanding mechanisms underlying malignancy. The multiple functions of RNA are accompanied by more than 100 chemical modifications the functions of most of these RNA modifications remain unclear [6] Among these modifications, adenosine N6 methylation (m6A) is considered to be the most common and conservative internal transcriptional modification in eukaryotic mRNAs [7]. The deletion of m6A methyltransferase METTL3 leads to selective splicing and gene expression alteration of >20 genes involved in the TP53 signaling pathway in hepatocellular carcinoma (HCC) [14]. We performed a retrospective analysis based on The Cancer Genome Atlas (TGCA) database to analyze genetic alterations involving m6A-related genes, their relationship with clinicopathological characteristics of HNSCC, and the prognostic value
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