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.
Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Epigenesis, Genetic/genetics , Pancreatic Neoplasms/genetics , Aged , Biomarkers, Tumor/genetics , DNA Methylation , Female , Humans , Immunohistochemistry , Male , Mutation , Polymerase Chain Reaction , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , Smad4 Protein/genetics , Statistics, Nonparametric , Tumor Suppressor Protein p53/genetics , ras Proteins/geneticsABSTRACT
Global expression profiling of pancreatic cancers has identified two cell surface molecules, claudin 4 and prostate stem cell antigen (PSCA), as being overexpressed in the vast majority of cases. Two antibodies, anti-claudin 4 and anti-PSCA, were radiolabeled with iodine 125 ((125)I) for imaging pancreatic cancer xenografts in mice using gamma scintigraphy and single-photon emission computed tomography-computed tomography (SPECT-CT). Immunofluorescence staining of intact and permeabilized Colo357 human pancreatic cancer cells showed strong extracellular staining by both anti-PSCA and anti-claudin 4. Biodistribution studies in claudin 4 and PSCA-expressing Colo357 and PANC-1 subcutaneous xenograft models in mice showed that [(125)I]anti-claudin 4 tumor to muscle ratio uptake was 4.3 in Colo357 at 6 days postinjection and 6.3 in PANC-1 xenografts at 4 days postinjection. Biodistribution of [(125)I]anti-PSCA showed tumor to muscle ratio uptake of 4.9 in Colo357 at 6 days postinjection. Planar gamma scintigraphic imaging in Colo357 xenograft-bearing mice showed clear tumor uptake of [(125)I]anti-claudin 4 by 24 hours postinjection and by 48 hours postinjection for [(125)I]anti-PSCA. SPECT-CT imaging with [(125)I]anti-claudin 4 and [(125)I]anti-PSCA in an L3.6PL orthotopic xenograft model showed strong tumor and spleen uptake at 5 days postinjection. Both anti-claudin 4 and anti-PSCA demonstrate promise as radiodiagnostic and possibly radiotherapeutic agents for human pancreatic cancers.
