Stephen G. Chun and Nelson S. Yee

Stephen G. Chun

Department of Surgery, John A. Burns School of Medicine; Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii

Nelson S. Yee

Corresponding author: nelson-yee@uiowa.edu
Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine, University of Iowa Program of Cell Signaling and Developmental Pharmacology, Holden Comprehensive Cancer Center, University of Iowa

Advanced age is considered a risk factor of 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 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.