Abstract
As the most prevalent type of mRNA modification in mammals, N6-methyladenosine (m6A) is involved in various biological processes. Accumulating studies have indicated that the deregulation of m6A RNA modification is linked to cancer and other diseases. However, its implications in hepatocellular carcinoma (HCC) remain poorly characterized. Herein, we sought to investigate the expression pattern of 13 key regulators for m6A RNA modification and to evaluate their prognostic value in HCC. First, we systematically analyzed data from The Cancer Genome Atlas (TCGA) database pertaining to patient clinical information and mRNA gene expression data. We found that 11 out of 13 key regulators for m6A RNA modification showed significantly higher expression levels in HCC. Subsequently, we identified two subgroups (clusters 1 and 2) via consensus clustering based on the expression of 13 m6A RNA methylation regulators. Cluster 2 had a worse prognosis and was also significantly correlated with higher histological grade and pathological stage when compared with cluster 1. Moreover, cluster 2 was remarkedly enriched for cancer-related pathways. We further constructed a robust risk signature of five regulators for m6A RNA modification. Further analysis indicated that this risk signature could be an independent prognostic factor for HCC, and the prognostic relevance of this five-gene risk signature was successfully validated using the Gene Expression Omnibus (GEO) dataset. Finally, we established a novel prognostic nomogram on the basis of age, gender, histological grade, pathological stage, and risk score to precisely predict the prognosis of patients with HCC. In summary, we herein uncovered the vital role of regulators for m6A RNA modification in HCC and developed a risk signature as a promising prognostic marker in HCC patients.
Highlights
Hepatocellular carcinoma (HCC) remains among the most prevalent and deadly types of cancer worldwide, with more than 700,000 deaths documented annually [1]
Heatmap clearly revealed that most of these m6Arelated genes were differentially expressed between HCC and control tissues (Figure 1A)
In order to evaluate whether the five-gene risk signature was independent from other clinicopathologic characteristics as a prognostic factor for HCC, we conducted multivariate Cox regression analyses, which demonstrated that both risk score and stage were independently correlated with overall survival (OS) for patients with HCC (Figure 7C, p < 0.001). These results demonstrated that the five-gene risk signature was able to predict prognosis independently of gender, age, histological grade and pathological stage, indicating that this five-gene risk signature could serve as an independent prognostic factor for HCC
Summary
Hepatocellular carcinoma (HCC) remains among the most prevalent and deadly types of cancer worldwide, with more than 700,000 deaths documented annually [1]. Even though the prognosis for HCC patients has improved due to recent advances in various treatment approaches, including surgical tumor resection, targeted drug therapy, transarterial chemoembolization, and liver transplantation, the 5-year survival rate remains dismal due to the high rate of metastasis and recurrence [4]. The tumor, lymph node, and metastasis (TNM) staging system is still the most widely adopted prognostic indicator for monitoring the progress of HCC. HCC is highly heterogeneous; patients with the same TNM stage often present remarkable differences in survival outcomes and treatment responses. To improve the unsatisfactory outcomes of patients with HCC, it is important to identify novel and reliable molecular signatures for prognostic prediction
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