Abstract

Introduction: Fibrosis, a primary cause of hepatocellular carcinoma (HCC), is intimately associated with inflammation, the tumor microenvironment (TME), and multiple carcinogenic pathways. Currently, due to widespread inter- and intra-tumoral heterogeneity of HCC, the efficacy of immunotherapy is limited. Seeking a stable and novel tool to predict prognosis and immunotherapy response is imperative. Methods: Using stepwise Cox regression, least absolute shrinkage and selection operator (LASSO), and random survival forest algorithms, the fibrosis-associated signature (FAIS) was developed and further validated. Subsequently, comprehensive exploration was conducted to identify distinct genomic alterations, clinical features, biological functions, and immune landscapes of HCC patients. Results: The FAIS was an independent prognostic predictor of overall survival and recurrence-free survival in HCC. In parallel, the FAIS exhibited stable and accurate performance at predicting prognosis based on the evaluation of Kaplan–Meier survival curves, receiver operator characteristic curves, decision curve analysis, and Harrell’s C-index. Further investigation elucidated that the high-risk group presented an inferior prognosis with advanced clinical traits and a high mutation frequency of TP53, whereas the low-risk group was characterized by superior CD8+ T cell infiltration, a higher TIS score, and a lower TIDE score. Additionally, patients in the low-risk group might yield more benefits from immunotherapy. Conclusion: The FAIS was an excellent scoring system that could stratify HCC patients and might serve as a promising tool to guide surveillance, improve prognosis, and facilitate clinical management.

Highlights

  • Fibrosis, a primary cause of hepatocellular carcinoma (HCC), is intimately associated with inflammation, the tumor microenvironment (TME), and multiple carcinogenic pathways

  • The coefficients of signature-1 were -0.13, 0.11, 0.12, and 0.16, respectively (Figure 2B). Another algorithm LASSO identified that signature-2 contained eight fibrosis-associated genes (FAGs), encompassing RPN2, MCM7, HMGA1, CAPG, SPP1, FCN3, IGFBP3, and GADD45B (Figure 2C)

  • The top 20 genes were recruited based on copy number amplification and deletion for each patient. Both amplification and deletion were not pronounced, meaning that similar copy number alteration (CNA) events existed in the two groups (Figures 6D,E). These results suggested that somatic mutation might have more crucial impacts on distinct prognosis and Hepatocellular carcinoma (HCC) progression compared to CNA

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Summary

Introduction

A primary cause of hepatocellular carcinoma (HCC), is intimately associated with inflammation, the tumor microenvironment (TME), and multiple carcinogenic pathways. Due to widespread inter- and intra-tumoral heterogeneity of HCC, the efficacy of immunotherapy is limited. The Barcelona Clinic Liver Cancer (BCLC) staging system is a basic measurement to evaluate risk and manage the prognosis of HCC patients (Villanueva, 2019). The current staging system is restricted to stratifying patients and may hinder optimal clinical decisions as HCC patients present significant heterogeneity (Craig et al, 2020). Searching for a new tool via multiple gene panels to stratify patients and further improve clinical management is imperative

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