The Identification and Validation of Two Heterogenous Subtypes and a Risk Signature Based on Ferroptosis in Hepatocellular Carcinoma.

Zaoqu Liu,Long Liu,Dechao Jiao,Yuling Sun,Libo Wang,Taoyuan Lu,Xinwei Han

doi:10.3389/fonc.2021.619242

Abstract

BackgroundFerroptosis is essential for tumorigenesis and progression of hepatocellular carcinoma (HCC). The heterogeneity of ferroptosis and its relationship with tumor microenvironment (TME) have still remain elusive.MethodsBased on 74 ferroptosis related genes (FRGs) and 3,933 HCC samples from 32 datasets, we comprehensively explored the heterogenous ferroptosis subtypes. The clinical significance, functional status, immune infiltration, immune escape mechanisms, and genomic alterations of different subtypes were further investigated.ResultsWe identified and validated two heterogeneous ferroptosis subtypes: C1 was metabolismlowimmunityhigh subtype and C2 was metabolismhighimmunitylow subtype. Compared to C2, C1 owned worse prognosis, and C1 tended to occur in the patients with clinical characteristics such as younger, female, advanced stage, higher grade, vascular invasion. C1 and C2 were more sensitive to immunotherapy and sorafenib, respectively. The immune escape mechanisms of C1 might be accumulating more immunosuppressive cells, inhibitory cytokines, and immune checkpoints, while C2 was mainly associated with inferior immunogenicity, defecting in antigen presentation, and lacking leukocytes. In addition, C1 was characterized by BAP1 mutation, MYC amplification, and SCD1 methylation, while C2 was characterized by the significant alterations in cell cycle and chromatin remodeling processes. We also constructed and validated a robust and promising signature termed ferroptosis related risk score (FRRS) for assessing prognosis and immunotherapy.ConclusionWe identified and validated two heterogeneous ferroptosis subtypes and a reliable risk signature which used to assess prognosis and immunotherapy. Our results facilitated the understood of ferroptosis as well as clinical management and precise therapy of HCC.

Highlights

Primary liver cancer is the sixth most prevalent malignant tumor worldwide and ranks fourth among the causes of tumor-related deaths, with approximately 840,000 new cases each year [1]
We evaluated the predictive performance of ferroptosis related risk score (FRRS) in three immunotherapy cohorts, and compared FRRS with seven other known biomarkers, including tumor mutation burden (TMB), TIDE, microsatellite instability (MSI) score, Merck18, IFGN, CD8, and CD274 [28, 34,35,36] (Table S4)
Further studies observed infrequent mutations of ferroptosis related genes (FRGs) and widespread copy number variations (CNVs), which suggested that CNVs might play a dominant role in the regulation of FRGs relative to mutation

Summary

Introduction

Primary liver cancer is the sixth most prevalent malignant tumor worldwide and ranks fourth among the causes of tumor-related deaths, with approximately 840,000 new cases each year [1]. Hepatocellular carcinoma (HCC) is major histological type (75– 85%) and characterized by high invasiveness and mortality rate [1]. Surgical resection is mainly performed for early HCC, but the 5-year recurrence rate is up to 70%, and most patients relapse within 2 years after surgery [2]. Patients with unresectable HCC usually receive the multi-kinase inhibitors such as sorafenib and lenvatinib, but drug-resistance and adverse reactions limit the survival benefit [3]. Great progress in immunotherapy represented by immune checkpoint inhibitors (ICI), only 25% of patients have durable responses [4, 5]. Even when combined with other treatment modalities such as local ablation and transcatheter arterial chemoembolization (TACE), the 5-year survival rate of patients is only 18% [6]. Ferroptosis is essential for tumorigenesis and progression of hepatocellular carcinoma (HCC). The heterogeneity of ferroptosis and its relationship with tumor microenvironment (TME) have still remain elusive

Methods

Results

Conclusion