A TTN-mutation-associated gene signature for prognostic prediction of hepatocellular carcinoma

Abstract

Background: Mutation in titin (TTN), associated with a worsened prognosis, is among the most common genetic variants in human hepatocellular carcinoma. mRNA expression data and TTN mutation information from TCGA cohort were utilized to characterize a specific TTN-mutation-associated signature according to gene-expression differences between wild type (TTN-WT) and TTN-mutated (TTN-MUT) hepatocellular carcinoma (HCC) patients. In total, 189 differentially expressed genes (DEGs) potentially correlated with TTN mutation status were identified. Five genes (VAX1, MMP3, CXCL5, TKTL1 and KCNA3), identified by univariate Cox regression and Kaplan-Meier survival analyses, constituted an independent OS prognostic gene signature in HCC patients. Depending on this gene signature, patients were grouped into high- and low-risk subgroups and a significant enrichment associated with immunity is detected between the risk groups. In addition, the high-risk group was associated with an abundance of macrophages and neutrophils, while the infiltration indices of T follicular helper cells, natural killer cells, and type 2 helper T cells (Th2) were lower compared to low-risk group. In the multivariate Cox regression model, the five-gene signature remained a significant predictor independent of other conventional clinical risk factors used for survival prediction in HCC patients. MMP3 and CXCL5 expression were further validated in HCC cell lines.Results: We established a novel and unique TTN-mutation-related gene signature for survival outcome prediction for HCC patients. Conclusion: Our research foundings display a specific mechanism of TTN mutation and hold promise for the identification of HCC patients with poor prognosis.