Hepatocellular carcinoma (HCC) - the most common type of primary liver cancer – is the sixth most common cancer globally and the third leading cause of cancer deaths worldwide. HCC incidence is increasing all around the world, with the incidence of HCC in developing countries already twice that of developed countries. Disease burden is particularly high in parts of Asia and Africa, coinciding with a high prevalence of chronic hepatitis B virus (HBV) infection. Likewise, mortality rates for HCC are also much higher in developing countries compared to developed countries.
All primary liver cancers start in the liver, with HCC malignancy specifically being found to begin in the parenchymal cells of the liver (hepatocytes). The tumour grows and progresses through local expansion, spreading within the liver (intahepatic spread) and distant metastases to other body organs.
The pathophysiology of HCC is multi-factoral, encompassing hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, cirrhosis (liver scarring), other liver disorders including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), type 2 diabetes, and lifestyle factors including obesity, smoking and heavy alcohol consumption.
Symptoms of HCC may sometimes only present during the advanced stages of disease, and may include pain or swelling in the upper-right quadrant and weight loss. However, earlier diagnosis is now possible due to the routine screening of patients with cirrhosis who are particularly vulnerable to developing primary liver cancer, such as those with NAFLD or NASH – both of which are becoming increasingly common, in part due to the rise in levels of obesity and type 2 diabetes.
Genetic and epigenetic changes in HCC carcinogenesis
Various recent studies have also revealed genetic pathways that may be linked to HCC using techniques such as whole genome sequencing, RNA sequencing and genome-wide methylation assays. HCCs typically have between 20-100 mutations per genome, with p53 and β-catenin being some of the most frequently mutated genes in HCC. The occurrence of these genomic mutations seem to be influenced by the underlying etiology of the liver cancer, for example infection with HBV or HCV.
Likewise, signalling pathways – particularly those involved in growth factor signalling, cellular differentiation and angiogenesis pathways – also appear to be involved in HCC pathogenesis. The Wnt/β-catenin pathway is commonly disrupted in HCC, with gene mutations which activate this pathway seen in up to 50% of HCCs.
Interestingly, epigenetic modifications (heritable modifications not due to DNA sequence) also contributes to HCC carcinogenesis. For example, chromatin remodelling can contribute to cancer initiation and progression, with recent studies showing that 18.2% of HCV-associated HCC patients in the US and Europe have inactivation mutations in chromatin remodelling gene ARID2.
HCC pathogenesis
The final common pathway in HCC pathogenesis includes repeated hepatocyte damage and a vicious cycle of cell death and regeneration that results in cirrhosis. This leads to genomic instability and HCC initiation, which progresses following the accumulation of genetic and epigenetic changes.
Pathogenesis of hepatocellular carcinoma figure available from 'Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances'.
As advances in next-generation sequencing continue to further our understanding of the genomic landscape of HCC, identifying mutations and molecular pathways commonly involved in HCC initiation and progression, we gain a deeper understanding of HCC pathogenesis which will be essential in discovering novel drug targets to tackle this malignancy.
Other resources:
Hepatocellular Carcinoma - Medscape
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