Development of N6-methyladenosine Related Signature as New Biomarker for Prognosis of Hepatocellular Carcinoma 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 expression profiles and prognostic values of 13 widely reported m6A modification related genes in HCC.Methods: 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 analysis was 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, 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 score, 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 high low score. Finally, significantly lower risk scores were found at sorafenib treatment responders and anti-PD-1 immunotherapy responders compared to that in non-responders, and anti-PD-1 immunotherapy treated patients with lower risk score had better OS than patients with higher risk score. Conclusion: A risk signature developed with the expression of 5 m6A related genes could improve the prediction of prognosis of HCC and correlate with sorafenib treatment and anti-PD-1 immunotherapy response.