title: Genetic and epigenetic alterations of familial pancreatic cancers.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Medicine, Oncology, Johns Hopkins Medical Institutions, The Sol Goldman Pancreatic Cancer Research Center, 1550 Orleans Street, CRB2, Room 342, Baltimore, MD 21231, USA.
authors.forename: Kieran
authors.initials: K
authors.lastname: Brune
authors.forename: Seung-Mo
authors.initials: SM
authors.lastname: Hong
authors.forename: Ang
authors.initials: A
authors.lastname: Li
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yachida
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Abe
authors.forename: Margaret
authors.initials: M
authors.lastname: Griffith
authors.forename: Dawei
authors.initials: D
authors.lastname: Yang
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Omura
authors.forename: James
authors.initials: J
authors.lastname: Eshleman
authors.forename: Marcia
authors.initials: M
authors.lastname: Canto
authors.forename: Rich
authors.initials: R
authors.lastname: Schulick
authors.forename: Alison P
authors.initials: AP
authors.lastname: Klein
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donohue
authors.forename: Michael
authors.initials: M
authors.lastname: Goggins
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D051901:Smad4 Protein / Q000235:genetics; D018709:Statistics, Nonparametric; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins