Tumor Mutational Burden for Predicting Prognosis and Therapy Outcome of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC), the primary hepatic malignancy, represents the second-highest cause of cancer-related death worldwide. Many efforts have been devoted to finding novel biomarkers for predicting both patients' survival and the outcome of pharmacological treatments, with a particular focus on immunotherapy. In this regard, recent studies have focused on unravelling the role of tumor mutational burden (TMB), i.e., the total number of mutations per coding area of a tumor genome, to ascertain whether it can be considered a reliable biomarker to be used either for the stratification of HCC patients in subgroups with different responsiveness to immunotherapy, or for the prediction of disease progression, particularly in relation to the different HCC etiologies. In this review, we summarize the recent advances on the study of TMB and TMB-related biomarkers in the HCC landscape, focusing on their feasibility as guides for therapy decisions and/or predictors of clinical outcome.

Keywords: hepatocellular carcinoma; immune checkpoint inhibitors; immunotherapy; liquid biopsy; microsatellite instability; neoantigens; tumor immune microenvironment; tumor mutational burden.

Figure 1

Multiple environmental factors, e.g., UV sunlight, smoke, mutagens, oxidative stress, persistent inflammation, and aging, prompt mutational burden of tumoral cells, increasing neoantigen processing and recognition of neoantigens by effector T cells.

Figure 2

Main cells populating the tumor microenvironment, i.e., monocyte-derived macrophages (MoMϕs) differentiating into tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumor-associated neutrophils (TANs), natural killer cells (NKs), regulatory T cells (Tregs), and cytotoxic CD8+ T (Teffector), as well as cancer-associated fibroblasts (CAFs), hepatic stellate cells (HSCs), and endothelial cells. TP53 and CTBBN1 are the two genes most frequently mutated showing a correlation with TMB.