Abstract
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 TP53, CTNNB1, and TERT 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 TP53 mutation, high FAL, and global hypomethylation was associated with aggressive tumor characteristics, like vascular invasion; CTNNB1 mutation was a feature of the less-progressive phenotype. A number of molecular risk factors, including TP53 mutation, high FAL, significant global hypomethylation, and absence of CTNNB1 mutation, were noted to predict shorter recurrence-free survival in patients who underwent liver transplantation (p = 0.0090 by log-rank test). These findings were validated in a cohort of resected HCC cases from TCGA (p = 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.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer-related death worldwide
Mutation of CTNNB1 was more frequently observed in HCCs from males (28/90, 31.1% for males, and 3/35, 8.6% for females; p = 0.0088 by Pearson’s chi-square test, Table 1)
Our analysis showed that the presence of TERT promoter mutation and hypermethylation in tumor suppressor genes (TSGs) promoters were associated with HCV presence, but not with characteristics related to tumor progression (Table 1)
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer-related death worldwide. Regorafenib, a tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) type 1 to 3, platelet-derived growth factor receptor, angiopoietin 2 receptor, KIT, and RET, is approved for HCC patients who have progressed on sorafenib, because of its effect on extension of overall survival (OS) and progression-free survival (PFS) [4]. This result suggests that sequential sorafenib/regorafenib treatment would be available in the advanced stage of HCCs, which could be beneficial for survival [5]
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