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Case Reports
. 2010 Sep 1;10(5):430-7.
doi: 10.4161/cbt.10.5.12763. Epub 2010 Sep 22.

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

Stephen G Chun  1 , Nelson S Yee
Affiliations
Case Reports

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

Stephen G Chun et al. Cancer Biol Ther. .

Abstract

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.

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Figures

Figure 1
Figure 1
The 43 year-old patient with WS developed accelerated aging with onset during the second decade of life and subsequently pancreatic adenocarcinoma. (A) on physical examination, the patient appeared older than his stated age and developed gray hair and “bird-like” facies due to atrophy of subcutaneous fat. (B) computed-tomographic image of the abdomen. The arrowhead points to the hypodense lesion/tumor in the head of pancreas. (C) histologic examination of the primary tumor in the pancreas revealed moderately-differentiated ductal adenocarcinoma.
Figure 2
Figure 2
A schematic diagram of WRN with the loss-of-function mutations identified in the 43-year-old patient who developed pancreatic adenocarcinoma. The WRN gene encodes a helicase of the RecQ family containing an exonuclease domain, and also possesses a transactivation domain (TAD), RecQ conserved domain (RQC), helicase and RNase D C-terminus domain (HRDC) and nuclear localization sequence (NLS). This patient possessed mutations 009 and 039 as defined by the Werner International Registry. Mutation 009 caused a stop codon at exon 9 through a cytosine-to-thymine transition (C1105T), leading to the substitution of arginine by a stop codon (R369stop), and resulting in the truncation of the helicase and exonuclease domains. Mutation 039 caused a guanine-to-cytosine transversion (G3139-1C) at the junction of intron 25 and exon 26, leading to the substitution of phenylalanine for glycine (G1047F), and resulting in a frameshift and insertion of a stop codon 14 amino acids distal to the nucleotide change that abolished the NLS domain. AA, amino acid; BP, DNA base pair.
Figure 3
Figure 3
A working model for the role of WRN in the multiple steps of pancreatic carcinogenesis. We propose that suppression of WRN expression by K-RAS activation contributes to telomere shortening and genomic instability that is observed in PanINs. WRN may also be silenced in PanINs through loss-of-heterozygosity, methylation of its CpG-promoter region, and the loss-of-function mutations seen in WS. DP C4, deleted in pancreatic cancer 4; BRCA2, the DN A repair enzyme causing hereditary breast and ovarian cancer syndrome. The illustrated diagram is modified and reprinted from Am J Pathol 2000, 156: 1821–1825 with permission from the American Society for Investigative Pathology. →, activates; ⊣, inhibits.
Figure 4
Figure 4
A working model for the role of WRN in the signaling pathways involved in pancreatic cancer cells. The epidermal growth factor receptor (EGFR) pathway is a key mediator of cellular proliferation and survival in exocrine pancreas and pancreatic adenocarcinoma. We propose that downregulation of WRN expression by oncogenic K-RAS signaling, DNA methyltransferases (DNMTs) or a loss-of-heterozygosity (LOH), contributes to cellular proliferation and survival in pancreatic neoplasia by preventing p53-mediated transcription of p21CDKN1A and promoting the NF-κB signaling cascade. EGFR, receptor dimer; AKT, a serine/threonine-specific protein kinase; DSB, double-stranded DN A break; ER K, extracellular-signal related kinases; IKK, IkB kinase; MEK, mitogen-activated protein kinase; RAF, a protein serine/threonine protein kinase. →, activates; ⊣, inhibits.
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