Pancreatic cancer is one of the most aggressive malignant neoplasms, with a 5-year survival rate of about 10% in the United States of America (USA) [1]. The negative prognosis is due to the insidious growth and non-specific symptoms up to its advanced stages, and also to the absence of sensitive and specific methods for an early diagnosis. Approximately 80–85% of pancreatic cancer cases are diagnosed in stage IV, when the patients can no longer benefit from curative surgery [1]. In a small proportion of individuals, pancreatic cancer is diagnosed in a localized stage, when surgical treatment is possible and recommended. In this situation, the 5-year survival rate can reach up to 20% [1].

Huang et al. reported higher incidence and mortality rates of pancreatic cancer in high-income countries ^[2][5]. This suggests the possible correlation between pancreatic cancer and lifestyle factors ^[3][2]. This malignancy is associated with several risk factors that fall into two broad categories, namely intrinsic and extrinsic factors (Table 1). Extrinsic risk factors are modifiable. The higher incidence of this malignancy in developed regions can also be explained by the increasing prevalence in such areas of modifiable risk factors, such as cigarette smoking, alcohol intake, and obesity ^[4][3].

• BRCA2, STK11, CDKN2A, PALB2;
• Low-penetrance gene: ABO blood group locus ^[7][8][10,11].

Intrinsic Risk Factors	Extrinsic Risk Factors
Hereditary	Diet
AB0 blood group	Obesity
Chronic pancreatitis	Tobacco
Cystic fibrosis	Coffee and alcohol consumption
Pancreatic cysts	Helicobacter pylori infection
Diabetes mellitus and insulin resistance	Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV)

About 10% of pancreatic cancer patients have a genetic susceptibility ^[6][9]. To date, scientists have identified several genes related to the development of this malignancy, namely:

• High-penetrance genes: 

Regarding the hereditary risk of developing pancreatic cancer, two main categories were defined:

• Patients with genetic syndromes at risk of developing malignancies, including pancreatic cancer (e.g., Li-Fraumeni syndrome, ataxia-telangiectasia syndrome, Peutz-Jeghers syndrome, Lynch II syndrome, etc.);
• Patients at risk of familial pancreatic cancer, without a specific molecular basis ^[9][12].

In addition, the existing data in the literature suggest the possible presence of germline mutations in the genes involved in the onset of this malignancy, even in the absence of a family history of pancreatic cancer ^[10][13]. Some studies identified an association between pancreatic cancer and AB0 blood type. The blood group is determined by the presence or absence of some antigens on the surface of erythrocytes. These antigens are glycoproteins that can also be expressed on the surface of other cell types, including pancreatic cells.  Chronic pancreatitis is characterized by a chronic inflammation of the pancreas, which can progress to pancreatic cancer ^[11][12][15,16]. Thus, among patients with chronic pancreatitis, a cumulative risk of progression to pancreatic cancer of 1.8% at 10 years and 4% at 20 years was reported, regardless of the type of pancreatitis ^[13][17]. There are also reports of the involvement of the cationic trypsinogen gene (PRSS1) in the etiopathogenesis of chronic pancreatitis and pancreatic cancer ^[14][19]. Somatic mutations of PRSS1 have been shown to play important roles in carcinogenesis ^[14][19]. The association of cystic fibrosis with some digestive cancers, including pancreatic cancer, has been demonstrated ^[15][20]. Cystic fibrosis is the most common autosomal recessive disease in Europe. It appears as a consequence of biallelic inactivating germline mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Other conditions strongly correlated with the risk of developing pancreatic cancer are pancreatic cysts, the most common types being intraductal papillary mucinous neoplasms (IPMN). Therapeutic management usually consists of carefully monitoring these patients for the early identification of possible malignant degeneration. In a surveillance strategy for IPMN, the appearance of pancreatic ductal adenocarcinoma was reported in 2–9% of patients, independent of the evolution of IPMN. These results suggest the existence of genetic defects in the pancreatic tissue ^[16][21]. The relationship between pancreatic cancer and diabetes mellitus is bidirectional. Thus, approximately 1% of patients over the age of 50 years, newly diagnosed with metabolic disorder, associate pancreatic cancer as a trigger for their diabetes ^[17][22]. 

2. Viral Hepatitis: Virology and Epidemiology

Viral hepatitis is a worldwide public health problem because of the large number of affected individuals and the morbidity and mortality rates associated with these infectious disorders. Among viruses responsible for hepatitis, the most important are the hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D (delta) virus (HDV), and hepatitis E virus (HEV) ^[18][53]. Of these, the only one that does not lead to chronic hepatitis is HAV, while HBV, HCV, HDV, and occasionally HEV may be responsible for long-term forms of viral liver infection ^[18][53].  HBV is a DNA virus, belonging to the Orthohepadnavirus genus, and is classified into 10 genotypes, A–J ^[19][56]. This virus can be transmitted sexually, by blood, and vertically, from the mother to the fetus ^[19][56]. HBV genotypes have several peculiarities in terms of geographical distribution, route of transmission, and organ damage ^[20][57].

3. Hepatotropic Viruses and Pancreatic Cancer-Pathophysiological Links

HBV and HCV are hepatotropic viruses with oncogenic properties. These viruses can induce persistent liver injury, with subsequent progression to cirrhosis and hepatocellular carcinoma ^[21][22][62,63]. There are also data suggesting the involvement of these viruses in the development of other neoplasms, such as pancreatic cancer, intrahepatic and extrahepatic duct bile carcinoma, gastric cancer, oesophageal cancer, certain forms of non-Hodgkin’s lymphoma, and leukemia ^{[23][24][25][26]}[64,65,66,67]. Anatomically, the pancreas is situated in the proximity of the liver. The common origin of the blood vessels and bile ducts of these organs makes possible the microorganisms’ migration ^[27][52]. Antigens and replicative sequences of these two viruses have also been identified in extrahepatic tissues (e.g., the pancreas, the kidneys, and the skin) ^[28][29][68,69]. Figure 12 summarizes the pathophysiological mechanisms by which hepatotropic viruses may contribute to the development of pancreatic cancer.