Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy

Abstract

The pathogenesis of hepatocellular carcinoma (HCC) is poorly understood, but recent advances in genomics have increased our understanding of the mechanisms by which hepatitis B virus, hepatitis C virus, alcohol, fatty liver disease, and other environmental factors, such as aflatoxin, cause liver cancer. Genetic analyses of liver tissues from patients have provided important information about tumor initiation and progression. Findings from these studies can potentially be used to individualize the management of HCC. In addition to sorafenib, other multi-kinase inhibitors have been approved recently for treatment of HCC, and the preliminary success of immunotherapy has raised hopes. Continued progress in genomic medicine could improve classification of HCCs based on their molecular features and lead to new treatments for patients with liver cancer.

Keywords: Epigenetics; HCC; Hepatitis; Immunotherapy; Tert.

Figure 1.. Pathogenesis of HCC

Liver cirrhosis is caused by chronic infection with HBV or HCV, alcohol abuse, or fatty liver disease. The chronic inflammation, necrosis, and regeneration that occur during development of cirrhosis cause genetic and epigenetic changes in liver tissue that lead to tumor formation. NASH, non-alcoholic steatohepatitis

Figure 2.. Genotype and Phenotype Classification of HCC

HCCs can be classified based on their genetic features, molecular features (S1 to S3, ref 134 and G1 to G6, ref 120) pathology features, signaling pathways activated, and clinical features of patients. Many of these subgroups overlap in their features. Chrom, chromosome.

Figure 3.. From Hepatocyte Transformation to Malignancy

Genetic changes that occur during transformation of hepatocytes in patients with and without cirrhosis. Mutations in the promoter region of TERT contribute to immortality and proliferation of hepatocytes, resulting in dysplastic nodules. Additional mutations, some induced by viruses such as HBV or AAV2, lead to early-stage HCC. Mutations in genes such as TP53, CTNNB1, and AXIN1 lead to advanced HCC, with additional chromosome alterations. Patients without cirrhosis exposed to high levels of estrogen, such as through oral contraceptives, are at increased risk for hepatic adenomas (HCA), which are benign but can progress to malignant tumors if cells acquire mutations in the same genes that contribute to HCC development. Red arrows indicate genetic alterations believed to be required for heptocarcinogenesis.

Figure 4.. Accumulation of Mutations During Liver Carcinogenesis

Mutation signatures of different subgroups of HCCs. Some signatures are found in a large proportion of HCCs (percentage values given) worldwide, whereas others are found in small proportions of HCCs, related to specific carcinogen exposures or in sporadic tumors. Lines of increasing width from left to right indicate mutations that accumulate with time, whereas straight lines from left to right indicate mutations that do not increase with time.