Identification of an m6A-Related Signature as Biomarker for Hepatocellular Carcinoma Prognosis and Correlates with Sorafenib and Anti-PD-1 Immunotherapy Treatment Response

Abstract

Background. N6-methyladenosine (m6A) modification plays an essential role in diverse key biological processes and may take part in the development and progression of hepatocellular carcinoma (HCC). Here, we systematically analyzed the expression profiles and prognostic values of 13 widely reported m6A modification-related genes in HCC. Methods. The mRNA expression of 13 m6A modification-related genes and clinical parameters of HCC patients were downloaded from TCGA, ICGC, GSE109211, and GSE78220. Univariate and LASSO analyses were used to develop risk signature. Time-dependent ROC was performed to assess the predictive accuracy and sensitivity of risk signature. Results. FTO, YTHDC1, YTHDC2, ALKBH5, KIAA1429, HNRNPC, METTL3, RBM15, YTHDF2, YTHDF1, and WTAP were significantly overexpressed in HCC patients. YTHDF1, HNRNPC, RBM15, METTL3, and YTHDF2 were independent prognostic factors for OS and DFS in HCC patients. Next, a risk signature was also developed and validated with five m6A modification-related genes in TCGA and ICGC HCC cohort. It could effectively stratify HCC patients into high-risk patients with shorter OS and DFS and low-risk patients with longer OS and DFS and showed good predictive efficiency in predicting OS and DFS. Moreover, significantly higher proportions of macrophages M0 cells, neutrophils, and Tregs were found to be enriched in HCC patients with high risk scores, while significantly higher proportions of memory CD4 T cells, gamma delta T cells, and naive B cells were found to be enriched in HCC patients with low scores. Finally, significantly lower risk scores were found at sorafenib treatment responders and anti-PD-1 immunotherapy responders compared to that in nonresponders, and anti-PD-1 immunotherapy-treated patients with lower risk scores had better OS than patients with higher risk scores. Conclusion. A risk signature developed with the expression of 5 m6A-related genes could improve the prediction of prognosis of HCC and correlated with sorafenib treatment and anti-PD-1 immunotherapy response.

m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in hepatocellular carcinoma

“…Sheng et al constructed an m6A-scoring signature in glioma that could predict therapeutic efficacy and patient prognosis [ 11 ]. Interestingly, another m6A scoring signature was associated with sorafenib treatment and anti-PD-1 immunotherapy response in HCC [ 33 ]. In our study, the m6Ascore was higher in HCC patients who had a good response to immunotherapy, including PD-1 and CTLA4, which could also account for the result that HCC patients with a high m6A-scoring had a better OS.…”

N6-Methyladenosine in Cancer Immunotherapy: An Undervalued Therapeutic Target

“…Moreover, low m 6 A score, characterized by increased mutation burden and activation of immunity, indicates an inflamed TME phenotype and enhanced response to anti-PD-1/L1 immunotherapy in gastric cancer (GC) (65). In addition, m 6 A-related signature has been identified as biomarker for tumor immune phenotypes and anti-PD-1 immunotherapy treatment response in lung adenocarcinoma (LADC) (72,73), stomach adenocarcinomas (STADs) (74), Esophageal squamous cell carcinoma (ESCC) (75,76), Renal Papillary Cell Carcinoma (RPCC), Hepatocellular Carcinoma (HCC) (77,78). These statistic results together indicate that m 6 A modification may reflect TME status and predict immunotherapy efficacy in pan-cancers instead of limited to specific cancer types.…”

Roles and mechanisms of the m6A reader YTHDC1 in biological processes and diseases

“…Liver cancer is a common cancer worldwide and it is estimated that in 2021 42,230 new cases and 30,230 deaths would be identified in the United States [ 19 ]. The YTHDC1 mRNA expression data was downloaded and analyzed from TCGA, ICGC, GSE109211 and GSE78220 by Jiang et al who revealed that YTHDC1 was significantly overexpressed in hepatocellular carcinoma patients [ 30 ]. Further analysis showed that the higher expression of YTHDC1 was statistically related to the poorer survival of hepatocellular carcinoma patients [ 30 ].…”

“…The YTHDC1 mRNA expression data was downloaded and analyzed from TCGA, ICGC, GSE109211 and GSE78220 by Jiang et al who revealed that YTHDC1 was significantly overexpressed in hepatocellular carcinoma patients [ 30 ]. Further analysis showed that the higher expression of YTHDC1 was statistically related to the poorer survival of hepatocellular carcinoma patients [ 30 ]. In another study concerning hepatocellular carcinoma, YTHDC1 favored the cytoplasmic export of m 6 A modified circHPS5 which acted as a miR-370 sponge to downregulate the expression of HMGA2 and thus accelerate the hepatocellular carcinoma tumorigenesis [ 31 ].…”