Construction and validation of an N6-methyladenosine-associated prognostic signature in hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC) is among the most common types of cancer that threat the public health worldwide. N6-methyladenosine (m6A) RNA methylation is associated with cancer initiation and progression, and is dynamically regulated by m6A RNA methylation-associated genes. However, little is known about the expression status and the prognostic value of m6A-associated genes in HCC. The present study aimed to identify the expression profiling pattern and clinical significance of m6A-associated genes in HCC. Consensus clustering analysis was performed to identify the clusters of HCC with different clinical outcomes. A prognostic signature built by the least absolute shrinkage and selection operator Cox regression model was utilized to discover subtypes associated with different clinical outcomes of patients with HCC in the discovery cohort from The Cancer Genome Atlas. The differences between subgroups were characterized in terms of epigenetic dysregulation and somatic mutation frequencies. The International Cancer Genome Consortium cohort and two independent cohorts from the meta-Gene Expression Omnibus database were used for external validation. Most of the m6A-associated genes were upregulated and involved in the prognosis and malignancy of HCC. A four-gene prognostic signature revealed two HCC subtypes (namely, high- and low-risk group) that was associated with different clinical outcomes. Patients in the high-risk group were accompanied with increased epigenetic silencing and significant mutations in TP53 and FLG, while ALB was frequently mutated in the low-risk group. In conclusion, an m6A-based signature was constructed to predict the prognosis of patients with HCC, which may provide a tool for reliable prognosis assessment for clinicians, and aid clinical treatment decision-making.