Werner's syndrome as a hereditary risk factor for exocrine pancreatic cancer: Potential role of WRN in pancreatic tumorigenesis and patient-tailored therapy

Stephen G. Chun, Nelson S. Yee

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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's 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.

Original languageEnglish (US)
Pages (from-to)430-437
Number of pages8
JournalCancer Biology and Therapy
Volume10
Issue number5
DOIs
StatePublished - Sep 1 2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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