Hepatocellular Carcinoma: Past and Present Challenges and Progress in Molecular Classification and Precision Oncology

Abstract

Hepatocellular carcinoma (HCC) is one of the most common solid tumor malignancies in the world and represents roughly 90% of all primary malignancies of the liver. The most common risk factors for HCC include hepatitis B virus, hepatitis C virus, alcohol, and increasingly, fatty liver. Most HCC is diagnosed at advanced stages, excluding the possibility of curative resection, which leaves systemic therapy as the only treatment option. However, given the extreme mutational diversity and heterogenous nature of HCC, efforts to develop new targeted systemic therapies were largely unsuccessful until recently. HCC pathogenesis is thought to be a multistage process driven by a wide array of nonmutually exclusive driver mutations accompanied by many passenger mutations, with the average tumor possessing approximately 40 genomic aberrations. Over the past two decades, several efforts to categorize HCC prognostically and therapeutically according to different molecular subclassifications with the intent to guide treatment and identify drug targets have emerged, though, no single consensus has been reached. Recent breakthroughs in drug development have greatly expanded treatment options, but the ideal of uniting each patient's unique HCC with a targeted systemic therapy remains elusive.

Keywords: genome; hepatocellular carcinoma; precision oncology; systemic therapy.

Figure 1

Simplified diagram outlining the main mechanisms of pathogenesis of hepatocellular carcinoma (HCC). In pathway (A), a morphologically normal liver is exposed chronically to pro-cirrhotic viruses or toxins. The most common risk factors are hepatitis B virus (HBV), hepatitis C virus, (HCV), alcohol, and aflatoxin. This exposure results in cirrhosis, which over time through chronic inflammation promotes the formation of low-grade dysplastic nodules (LGDN), which then progress to high-grade dysplastic nodules (HGDN). The altered cellular and immune environment of the cirrhotic liver causes accumulation of driver and passenger mutations and finally the development of frank HCC. In pathway (B), an alternative and growing share of HCC development occurs through fatty liver disease, which generates more oxidative stress as the disease progresses. This oxidative stress then leads to cirrhosis by which, similar to pathway (A), chronic inflammation promotes the development of LGDN that transform into HGDN and eventually HCC due to similar alterations of the immune and cellular environment of the cirrhotic and chronically inflamed liver. Created using Biorender.com.