Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors

Tumors of the endocrine pancreas are extremely rare, and molecular mechanis ms leading to their development are not well understood, ii candidate tumor suppressor gene, DPC4, located at 18q21, has recently been shown to be ina ctivated in half of pancreatic adenocarcinoma xenografts, The close anatomi cal relationship of the exocrine and endocrine pancreas prompted us to dete rmine the role of DPC4 in the tumorigenesis of 25 pancreatic islet cell tum ors (II insulinomas, nine nonfunctioning endocrine carcinomas, three gastri nomas, two vipomas). A mutation screening of the highly conserved COOH-term inal domain of DPC4 (exons 8-11) was performed by single-strand conformatio nal variant (SSCP) analysis and a PCR-based deletion assay. Five of nine (5 5%) non-functioning endocrine pancreatic carcinomas revealed either point m utations, small intragenic deletions or homozygous deletion of DPC4 sequenc es compared to none of the insulinomas, gastrinomas or vipomas, These resul ts suggest that DPC4 is an important target gene promoting tumorigenesis of non-functioning neuroendocrine pancreatic carcinomas.