Advanced age is considered a risk factor for pancreatic cancer, but this relationship at the molecular and genetic level
remains unclear. We present a clinical case series focusing on an association between pancreatic adenocarcinoma and
Werner syndrome (WS) that is an autosomal recessive genetic disorder characterized by accelerated aging and cancer
predisposition, and is caused by loss-of-function mutations in the WS RecQ helicase gene (WRN). Although pancreatic
adenocarcinoma mostly occurs in a sporadic fashion, a minority of cases occurs in the context of susceptible individuals
with hereditary syndromes. While WS has not been previously recognized as a risk factor for developing malignant
tumors of the exocrine pancreas, the clinicopathologic features of three reported patients suggest a contributory role of
WRN deficiency in pancreatic carcinogenesis. Molecular genetic analyses support the role of WRN as a tumor suppressor
gene, although recent evidence reveals that WRN can alternatively promote oncogenicity depending on the molecular
context. Based upon the clinico-pathologic features of these patients and the role of WRN in experimental models,
we propose that its loss-of-function predisposes the development of pancreatic adenocarcinoma through epigenetic
silencing or loss-of-heterozygosity of WRN. To test this hypothesis, we are investigating the mechanistic role of WRN
in pancreatic cancer models including a pancreatic adenocarcinoma cell line generated from a human with WS. These
studies are expected to provide new insight into the relationship between aging and pancreatic tumorigenesis, and
facilitate development of novel strategies for patient-tailored interventions in this deadly malignancy.