Abstract
Background: Due to the heterogeneity of tumors and the complexity of the immune microenvironment, the specific role of ferroptosis and pyroptosis in hepatocellular carcinoma (HCC) is not fully understood, especially its impact on prognosis.Methods: The training set (n = 609, merged by TCGA and GSE14520) was clustered into three subtypes (C1, C2, and C3) based on the prognosis-related genes associated with ferroptosis and pyroptosis. The intersecting differentially expressed genes (DEGs) among C1, C2, and C3 were used in univariate Cox and LASSO penalized Cox regression analysis for the construction of the risk score. The median risk score served as the unified cutoff to divide patients into high- and low-risk groups.Results: Internal (TCGA, n = 370; GSE14520, n = 239) and external validation (ICGC, n = 231) suggested that the 12-gene risk score had high accuracy in predicting the OS, DSS, DFS, PFS, and RFS of HCC. As an independent prognostic indicator, the risk score could be applicable for patients with different clinical features tested by subgroup (n = 26) survival analysis. In the high-risk patients with a lower infiltration abundance of activated B cells, activated CD8 T cells, eosinophils, and type I T helper cells and a higher infiltration abundance of immature dendritic cells, the cytolytic activity, HLA, inflammation promotion, and type I IFN response in the high-risk group were weaker. The TP53 mutation rate, TMB, and CSC characteristics in the high-risk group were significantly higher than those in the low-risk group. Low-risk patients have active metabolic activity and a more robust immune response. The high- and low-risk groups differed significantly in histology grade, vascular tumor cell type, AFP, new tumor event after initial treatment, main tumor size, cirrhosis, TNM stage, BCLC stage, and CLIP score.Conclusion: The ferroptosis and pyroptosis molecular subtype-related signature identified and validated in this work is applicable for prognosis prediction, immune microenvironment estimation, stem cell characteristics, and clinical feature assessment in HCC.
Highlights
Due to the heterogeneity of tumors and the complexity of the immune microenvironment, the specific role of ferroptosis and pyroptosis in hepatocellular carcinoma (HCC) is not fully understood, especially its impact on prognosis
Ferroptosis and Pyroptosis Molecular Subtype Was Related to the Prognosis of Hepatocellular Carcinoma
We found that the intergroup correlations were lowest and the intragroup correlations were the highest when k = 3 by increasing the clustering variable (k) from 2 to 9, indicating that the training cohort (n = 609, merged by The Cancer Genome Atlas (TCGA) and GSE14520) could be well clustered into three subtypes based on the 99 prognostic related genes associated with ferroptosis and pyroptosis (Figures 1B,C)
Summary
Due to the heterogeneity of tumors and the complexity of the immune microenvironment, the specific role of ferroptosis and pyroptosis in hepatocellular carcinoma (HCC) is not fully understood, especially its impact on prognosis. The occurrence of pyroptosis mainly depends on inflammatory caspases and the GSDM protein family (Bergsbaken et al, 2009). Activated caspase cleaves GSDM proteins and releases their N-terminal domain, which binds to membrane lipids and makes holes in the cell membrane. This causes a change in cell osmotic pressure, and the cell swells until its membrane ruptures, which leads to the release of the cell contents. The pathological features of ferroptosis are mainly the accumulation of iron-dependent lipid peroxides, and the typical morphological manifestations are cell volume shrinkage and an increase in mitochondrial membrane area. The mechanism is mainly related to a disorder of iron metabolism, an imbalance of the amino acid antioxidant system and the accumulation of lipid peroxide (Dixon et al, 2012)
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