Genetic and epigenetic alterations of familial pancreatic cancers.
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.
Brune
Kieran
K
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.
Hong
Seung-Mo
SM
Li
Ang
A
Yachida
Shinichi
S
Abe
Tadayoshi
T
Griffith
Margaret
M
Yang
Dawei
D
Omura
Noriyuki
N
Eshleman
James
J
Canto
Marcia
M
Schulick
Rich
R
Klein
Alison P
AP
Hruban
Ralph H
RH
Iacobuzio-Donohue
Christine
C
Goggins
Michael
M
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
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