Repeated pancreatic injury can lead to chronic pancreatitis, increasing risk of malignant transformation. Hereditary pancreatitis (HP) is an extremely rare condition with an estimated prevalence of 3 in 1,000,000 people [
93]. HP patients have 50 to 70 times relative risk for PDAC compared with general population [
94] and they usually develop PDAC about 20 years earlier [
95]. It is estimated that 30% to 40% of HP affected individuals will develop PDAC by the age of 70 [
94].
PRSS1 (protease, serine 1) gene, which encodes cationic trypsinogen, is the main gene related to HP. In fact, it is calculated that near 80% of patients with HP have pathogenic variants in
PRSS1 [
96].
PRSS1 gene mutations are inherited in an autosomal dominant manner, generating a scenario where activated trypsin cannot be degraded and/or activation of trypsinogen into trypsin is stimulated, leading to inflammation and pancreas self-destruction [
97].
SPINK1 (serine peptidase inhibitor, Kazal type 1) gene, which encodes a trypsin inhibitor that is secreted by the pancreatic acinar cells, is also related to HP [
98]. Since the majority of
SPINK1 mutations are inherited in an autosomal recessive pattern, some of them may be inherited in an autosomal dominant manner [
99]. Besides, we must consider cystic fibrosis, caused by mutations in
CFTR gene, in differential diagnosis of HP. It is estimated that 1.5% of all patients with cystic fibrosis will suffer from pancreatitis, potentially increasing risk of PDAC development [
100,
101].