The landscape of gene mutations in cirrhosis and hepatocellular carcinoma

Abstract

Chronic liver disease and primary liver cancer are a massive global problem, with a future increase in incidences predicted. The most prevalent form of primary liver cancer, hepatocellular carcinoma, occurs after years of chronic liver disease. Mutations in the genome are a causative and defining feature of all cancers. Chronic liver disease, mostly at the cirrhotic stage, causes the accumulation of progressive mutations which can drive cancer development. Within the liver, a Darwinian process selects out dominant clones with selected driver mutations but also leaves a trail of passenger mutations which can be used to track the evolution of a tumour. Understanding what causes specific mutations and how they combine with one another to form cancer is a question at the heart of understanding, preventing and tackling liver cancer. Herein, we review the landscape of gene mutations in cirrhosis, especially those paving the way toward hepatocellular carcinoma development, that have been characterised by recent studies capitalising on technological advances in genomic sequencing. With these insights, we are beginning to understand how cancers form in the liver, particularly on the background of chronic liver disease. This knowledge may soon lead to breakthroughs in the way we detect, diagnose and treat this devastating disease.

Efficacy and safety of lenvatinib for patients with advanced hepatocellular carcinoma: A retrospective, real-world study conducted in China

“…The inhibitory potential of fibroblast growth factor receptor (FGFR) 1-4 in lenvatinib is different to that in sorafenib and is possibly the reason for the observed improvement in the overall effect[ 22 ]. In this study, the results of the gene mutation analysis were consistent with the published mutational landscape of HCC[ 23 , 24 ].…”

Hepatocellular carcinoma: old friends and new tricks

“…The Wnt/β-catenin pathway is a key developmental pathway that regulates liver homeostasis and zonation 89,90 . Approximately 15-33% of HCC patients carry activating mutations in β-catenin (CTNNB1) 91,92 , and 17% carry inactivating mutations in Axin1 (AXIN1; 11-15%) or adenomatous polyposis coli (APC; 1-2%) 19,83,93 . Mutations targeting these components prevent β-catenin degradation, which leads to aberrant Wnt signaling activation.…”

“…SWI/SNF complex genes exhibit strong tissue specificity, and specific mutations are enriched in different cancers. AT-rich interaction domain 1A (ARID1A) and ARID2 are core components of two separate subunits of SWI/SNF complexes (BAF and PBAF, respectively), and they are recurrently mutated in HCC (5-15% and 3-15%, respectively) 92 . ARID1A mutations are significantly associated with CTNNB1 mutations and alcohol-induced HCC 19 , and ARID2 mutations cooccur with NFE2L mutations 104 .…”

The cellular origins of cancer with particular reference to the gastrointestinal tract

“…In many other cases, we cannot be sure where the malignant tumour arose along the HPC/ductular cell/premalignant stage pathway. For example, liver cirrhosis is a premalignant condition with already a substantial mutational burden, 125 and mtDNA analysis shows that many nodules are monoclonal and derived from ductular cells. 126 If HCC arises within a cirrhotic nodule, what is its cell of origin, an HPC or a nodular hepatocyte?…”