Genetics and epigenetics of liver cancer

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, ranking as the sixth most frequently diagnosed cancer and the fourth leading cause of cancer-related deaths globally. The development of HCC arises from a complex interplay of genetic mutations and frequent epigenetic modifications. Key genetic contributors include mutations in tumor suppressor genes such as p۵۳ and RB, along with oncogenes like CTNNB۱. Additionally, epigenetic alterations, including aberrant DNA methylation and histone modifications, play a crucial role in HCC progression. The primary risk factors associated with HCC encompass chronic infections with hepatitis B virus (HBV) or hepatitis C virus (HCV), consumption of aflatoxin-contaminated food, heavy alcohol use, and type ۲ diabetes. This review specifically examines hepatocarcinogenesis instigated by HBV and HCV. The genetic mechanisms through which HBV and HCV lead to hepatocellular carcinoma involve a multifaceted interaction that includes viral integration, mutations induced by chronic inflammation, the influence of oncogenic viral proteins, and various epigenetic modifications. Collectively, these factors contribute to genomic instability and the dysregulation of essential cellular pathways, ultimately facilitating the development of HCC. The epigenetic mechanisms by which HBV and HCV contribute to hepatocellular carcinoma involve a complex interplay of DNA methylation, histone modifications, and non-coding RNA regulation. These mechanisms result in the silencing of tumor suppressor genes, activation of oncogenes, and overall genomic instability, thereby promoting the progression to HCC. Following HBV infection, a cascade of events occurs, including hepatocyte injury, chronic necro-inflammation, hepatocyte proliferation, fibrosis, and ultimately cirrhosis. The increased turnover of hepatocytes in cirrhosis, combined with the accumulation of mutations in the host genome, may lead to both genetic and epigenetic alterations, chromosomal aberrations, activation of oncogenes, and inactivation of tumor suppressor genes. Notably, HBV infection can also induce HCC directly, even in the absence of preceding cirrhosis. The integration of HBV into the host genome results in chromosomal rearrangements, further enhancing genomic instability. Additionally, HBV encodes a regulatory protein known as HBx, which transactivates specific genes involved in cell proliferation regulation, including Ras, Raf, MAPK, ERK, and JNK. Furthermore, HBx suppresses genes associated with cell cycle control, cellular DNA repair, and apoptosis, such as p۵۳. HBV can also induce changes in DNA methylation patterns, affecting gene expression and contributing to tumorigenesis. In contrast to HBV, HCV does not integrate into the host genome and thus causes HCC indirectly, with cirrhosis being a hallmark of its progression. The mechanisms underlying HCC development due to HCV infection are complex and involve various pathways associated with the interaction between the host response and the virus. HCV encodes several proteins, including core protein, NS۳/۴A proteins, and NS۵A protein, which can directly influence cellular pathways related to cancer development.

کلیدواژه ها:

Hepatocellular carcinoma ، HCV ، HBV ، Genetic mutations ، Epigenetic alterations