DPC4/Smad4: no mutations, rare allelic imbalances, and retained protein expression in pancreatic endocrine tumors

Several chromosomal loci involved in tumorigenesis of pancreatic endocrine tumors (PET) have been identified. To date, the only gene known to be frequently altered is the MEN1 gene. Recently, DPC4 mutations and homozygous deletions have been described in 5/9 (55%) non-functioning PET, thus representing the most frequent genetic aberration described in PET. However, these data are in discordance with comparative genomic hybridization (CGH) results that rarely show genetic losses on chromosome 18. They have also been challenged by immunohistochemical data. We performed a detailed combined DPC4 mutation and deletion analysis in 34 benign and malignant PET. Mutations of the conserved C-terminal exons were not found in all examined PET and allelic loss (LOH) was found to be rare (<6%) by combined microsatellite PCR and FISH analysis. In addition, DPC4 protein expression was retained in all PET that were examined by immunohistochemistry. Therefore, DPC4 inactivation by mutation or deletion appears to be very rare in PET, which confirms the current concept of unrelated mechanisms of tumorigenesis of endocrine versus exocrine pancreatic tumors.