Genetic and epigenetic alterations of familial pancreatic cancers

Kieran Brune, Seung Mo Hong, Ang Li, Shinichi Yachida, Tadayoshi Abe, Margaret Griffith, Dawei Yang, Noriyuki Omura, James Eshleman, Marcia Canto, Rich Schulick, Alison P. Klein, Ralph H. Hruban, Christine Iacobuzio-Donohue, Michael Goggins

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Little is known about the genetic and epigenetic changes that contribute to familial pancreatic cancers. The aim of this study was to compare the prevalence of common genetic and epigenetic alterations in sporadic and familial pancreatic ductal adenocarcinomas. Methods: DNA was isolated from the microdissected cancers of 39 patients with familial and 36 patients with sporadic pancreatic adenocarcinoma. KRAS2 mutations were detected by BstN1 digestion and/or cycle sequencing. TP53 and SMAD4 status were determined by immunohistochemistry on tissue microarrays of 23 archival familial pancreatic adenocarcinomas and in selected cases by cycle sequencing to identify TP53 gene mutations. Methylation-specific PCR analysis of seven genes (FoxE1, NPTX2, CLDN5, P16, TFPI-2, SPARC, ppENK) was done on a subset of fresh-frozen familial pancreatic adenocarcinomas. Results: KRAS2 mutations were identified in 31 of 39 (80%) of the familial versus 28 of 36 (78%) of the sporadic pancreatic cancers. Positive immunolabeling for p53 was observed in 57% of the familial pancreatic cancers and loss of SMAD4 labeling was observed in 61% of the familial pancreatic cancers, rates similar to those observed in sporadic pancreatic cancers. The mean prevalence of aberrant methylation in the familial pancreatic cancers was 68.4%, which was not significantly different from that observed in sporadic pancreatic cancers. Conclusion: The prevalence of mutant KRAS2, inactivation of TP53 and SMAD4, and aberrant DNA methylation of a seven-gene panel is similar in familial pancreatic adenocarcinomas as in sporadic pancreatic adenocarcinomas. These findings support the use of markers of sporadic pancreatic adenocarcinomas to detect familial pancreatic adenocarcinomas.

Original languageEnglish (US)
Pages (from-to)3536-3542
Number of pages7
JournalCancer Epidemiology Biomarkers and Prevention
Volume17
Issue number12
DOIs
StatePublished - Dec 2008

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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