Specific features of ß-catenin-mutated hepatocellular carcinomas

Abstract

CTNNB1, encoding the ß-catenin protein, is a key oncogene contributing to liver carcinogenesis. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer in adult, representing the third leading cause of cancer-related death. Aberrant activation of the Wnt/ß-catenin pathway, mainly due to mutations of the CTNNB1 gene, is observed in a significant subset of HCC. In this review, we first resume the major recent advances in HCC classification with a focus on CTNNB1-mutated HCC subclass. We present the regulatory mechanisms involved in β-catenin stabilisation, transcriptional activity and binding to partner proteins. We then describe specific phenotypic characteristics of CTNNB1-mutated HCC thanks to their unique gene expression patterns. CTNNB1-mutated HCC constitute a full-fledged subclass of HCC with distinct pathological features such as well-differentiated cells with low proliferation rate, association to cholestasis, metabolic alterations, immune exclusion and invasion. Finally, we discuss therapeutic approaches to target ß-catenin-mutated liver tumours and innovative perspectives for future drug developments.