Molecular Scoring of Hepatocellular Carcinoma for Predicting Metastatic Recurrence and Requirements of Systemic Chemotherapy

Hepatocellular carcinoma (HCC) causes one of the most frequent cancer-related deaths; an HCC subset shows rapid progression that affects survival. We clarify molecular features of aggressive HCC, and establish a molecular scoring system that predicts metastasis after curative treatment. In total, 125 HCCs were examined for <i>TP53</i>, <i>CTNNB1</i>, and <i>TERT</i> promoter mutation, methylation of 8 tumor suppressor genes, and 3 repetitive DNA sequences to estimate promoter hypermethylation and global hypomethylation. A fractional allelic loss (FAL) was calculated to represent chromosomal instability through microsatellite analysis. Molecular subclasses were determined using corresponding and hierarchical clustering analyses. Next, twenty-five HCC patients who underwent liver transplantation were analyzed for associations between molecular characteristics and metastatic recurrence; survival analyses were validated using a publicly available dataset of 376 HCC cases from the Cancer Genome Atlas (TCGA). An HCC subtype characterized by <i>TP53</i> mutation, high FAL, and global hypomethylation was associated with aggressive tumor characteristics, like vascular invasion; <i>CTNNB1</i> mutation was a feature of the less-progressive phenotype. A number of molecular risk factors, including <i>TP53</i> mutation, high FAL, significant global hypomethylation, and absence of <i>CTNNB1</i> mutation, were noted to predict shorter recurrence-free survival in patients who underwent liver transplantation (<i>p</i> = 0.0090 by log-rank test). These findings were validated in a cohort of resected HCC cases from TCGA (<i>p</i> = 0.0076). We concluded that molecular risks determined by common genetic and epigenetic alterations could predict metastatic recurrence after curative treatments, and could be a marker for considering systemic therapy for HCC patients.