**4. Common risk factors for HCC**

The major common risk factors for HCC are hepatic virus infection with HBV and HCV. Fatty liver disease, related or unrelated to alcohol abuse which frequently lead to liver cirrhosis, is the other major condition, increasing the risk for developing HCC (**Figure 1**).

#### **4.1. Hepatitis B virus (HBV) infection**

HBV is one of the most common etiologic factors leading to HCC worldwide. The risk of developing HCC is more than 15-fold in patients with HBV chronic infection [2, 14]. In most developed countries, around of 10% of HCC is associated with HBV infection which occurs through either parental contact with infected blood or sexual transmission. In contrast, other geographic regions in the world where HBV is endemic such as sub-Saharan Africa and Asia, HBV transmission occurs mainly via perinatal exposure [15, 16].

in sub-Saharan Africa, Mediterranean regions, and South America [17]. At least eight HDV genotypes, geographically distributed in different regions of the globe, have been reported. An estimated 20 millions of people are infected with one of HDV genotype. In combination with HBV infection, HDV precipitates liver failure and HCC [18]. The best treatment for HDV

**Figure 1.** Risk factors and current therapies of liver cancer. Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. A. Hepatocytes, the main liver cells are subjected to harmful conditions (hepatitis virus infections) causing hepatitis and frequently leading to cirrhosis and ultimately to HCC. Many treatment options are currently available for

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HCC. B. Gross anatomy and histology of healthy liver and liver diseases related to cirrhosis and HCC.

Currently, 10 HBV genotypes have been described. Apparently, HBV-infected patients with C and D genotypes develop more frequently liver cirrhosis and HCC than HBV patients,

infection is the eradication of HBV through HBV vaccine.

HBV patients are highly prone to secondary infection with hepatitis D virus (HDV). The HDV is dependent on HBV genome products to form its own. Infection with HDV is more frequent

**2. Epigenetic of HCC**

4 Liver Cancer

**3. Immunogenicity of HCC**

**4. Common risk factors for HCC**

**4.1. Hepatitis B virus (HBV) infection**

immunotherapy [9, 10].

Epigenetic modifications are crucial in HCC. They arise in the context of known risk factors leading to chronic liver disease and concern mostly chemical alterations of DNA and histones. DNA methylation is the commonly investigated, showing its relevance in the mechanisms of gene silencing. Currently, genome-wide methylation analysis indicates important changes in the methylation status of oncogenes, signaling molecules, and suppressor genes [8]. Therefore,

Tumor immunogenicity of HCC has been first demonstrated by using autologous tumor lysate and dendritic cells for the prevention of recurrence in HCC patients. Subsequently, several tumor-associated antigens (SART2, CypB, SART3, AFP p53, MRP3, and hTERT) have been identified and characterized in HCC, suggesting the development of highly effective

The modulation of immune costimulatory molecules has been also shown to play critical role in the pathogenicity of the liver. The costimulatory ligand member B7 is a crucial immune checkpoint in HCC [11]. B7-1, B7-2, B7-DC, and B7-H1 are expressed on professional antigenpresenting cells and regulate T cell activation after the binding with CD28, CTLA-4, or PD-1. B7-H3 is expressed in human HCC cells and is associated with tumor aggressiveness and postoperative recurrence [12]. Apparently, B7-H3 promotes aggression and invasion of HCC by targeting epithelial-to-mesenchymal transition via JAK2/STAT3/Slug signaling pathway [13].

The major common risk factors for HCC are hepatic virus infection with HBV and HCV. Fatty liver disease, related or unrelated to alcohol abuse which frequently lead to liver cirrhosis, is

HBV is one of the most common etiologic factors leading to HCC worldwide. The risk of developing HCC is more than 15-fold in patients with HBV chronic infection [2, 14]. In most developed countries, around of 10% of HCC is associated with HBV infection which occurs through either parental contact with infected blood or sexual transmission. In contrast, other geographic regions in the world where HBV is endemic such as sub-Saharan Africa and Asia,

HBV patients are highly prone to secondary infection with hepatitis D virus (HDV). The HDV is dependent on HBV genome products to form its own. Infection with HDV is more frequent

the other major condition, increasing the risk for developing HCC (**Figure 1**).

HBV transmission occurs mainly via perinatal exposure [15, 16].

targeting the epigenome could lead to novel therapies of HCC.

**Figure 1.** Risk factors and current therapies of liver cancer. Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. A. Hepatocytes, the main liver cells are subjected to harmful conditions (hepatitis virus infections) causing hepatitis and frequently leading to cirrhosis and ultimately to HCC. Many treatment options are currently available for HCC. B. Gross anatomy and histology of healthy liver and liver diseases related to cirrhosis and HCC.

in sub-Saharan Africa, Mediterranean regions, and South America [17]. At least eight HDV genotypes, geographically distributed in different regions of the globe, have been reported. An estimated 20 millions of people are infected with one of HDV genotype. In combination with HBV infection, HDV precipitates liver failure and HCC [18]. The best treatment for HDV infection is the eradication of HBV through HBV vaccine.

Currently, 10 HBV genotypes have been described. Apparently, HBV-infected patients with C and D genotypes develop more frequently liver cirrhosis and HCC than HBV patients, infected with the other genotype strains. Furthermore, those patients respond poorly to current therapies based on interferon or other antiviral agents [15, 16].

induce hepatitis: hepatitis A virus (HAV), hepatitis E virus (HEV), and hepatitis G virus (HGV). However, HBV and HCV are the most common inducers of hepatitis-related virus infections. People chronically infected with both hepatitis B and C present higher risk for

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Besides hepatitis virus infection and fatty liver disease related or unrelated to alcohol consumption, aflatoxin has been shown to increase the risk of developing HCC [28]. Aflatoxin is a family of fungus toxins that could be present at high levels in frequently consumed food such as nuts, grains, and spices that are not adequately selected or properly stored. Aflatoxin enters the food supply and can be found in animal and human-processed foods. Animals can pass aflatoxin derivative products into milk, eggs, and meat. Overweight and obesity constitute other independent risk factors for HCC. Therefore, in order to efficiently prevent hepatitis and HCC, raising awareness through general public education should be highly supported [29].

Currently, many options are available for the treatment of HCC [30]. Potentially curative treatments like surgical resection or liver transplantation might be possible for less advanced HCC. Minimally invasive surgical technologies continue to improve increasing its safety and applicability for oncologic liver surgery. Different surgical procedures, including advanced

Unfortunately, tumor recurrence and metastasis frequently occur after resection and limit the overall survival. In patients with unresectable HCC and preserved liver function, transarterial chemoembolization (TACE) can prolong survival. However, TACE is rarely curative. More than half of patients with HCC continue to die secondary to liver failure from progressing cirrhosis. Current chemotherapy, interferon treatment, or alternative medicine only partially benefits patients with advanced disease. Therefore, novel treatments for liver cancer, particu-

Since the introduction of sorafenib, a multikinase inhibitor that showed some benefits to HCC patients, other targeted and immune therapies emerged for the treatment of HCC. Currently, promising therapies for HCC are underway, including targeted therapy, immune checkpoint inhibitors, oncolytic viruses (OVs), and chimeric antigen receptor-redirected T cells (CAR-T cells). Combination strategies are also under investigation to promote further the treatment

HCC patients with advanced disease, not eligible for currently curative procedures, particularly surgery or local interventions, were selected to test the efficacy of immune checkpoint inhibitors in clinical trials [11]. CTLA-4 blockade with tremelimumab showed a high promise

developing HCC.

**6. Treatment options for HCC**

surgical technologies, are currently performed.

larly advanced HCC, are in urgent need [31].

**7. Emergence of immune checkpoint inhibitors**

of advanced HCC [32].
