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Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors
D Bartsch1, S A Hahn, K D Danichevski
1Department of Surgery, Philipps-University Marburg, Germany.
Abstract:
Tumors of the endocrine pancreas are extremely rare, and molecular mechanisms leading to their development are not well understood. A candidate tumor suppressor gene, DPC4, located at 18q21, has recently been shown to be inactivated in half of pancreatic adenocarcinoma xenografts. The close anatomical relationship of the exocrine and endocrine pancreas prompted us to determine the role of DPC4 in the tumorigenesis of 25 pancreatic islet cell tumors (11 insulinomas, nine non-functioning endocrine carcinomas, three gastrinomas, two vipomas). A mutation screening of the highly conserved COOH-terminal domain of DPC4 (exons 8-11) was performed by single-strand conformational variant (SSCP) analysis and a PCR-based deletion assay. Five of nine (55%) non-functioning endocrine pancreatic carcinomas revealed either point mutations, small intragenic deletions or homozygous deletion of DPC4 sequences compared to none of the insulinomas, gastrinomas or vipomas. These results suggest that DPC4 is an important target gene promoting tumorigenesis of non-functioning neuroendocrine pancreatic carcinomas.
Insights
The DPC4 gene is frequently altered in non-functioning neuroendocrine pancreatic carcinomas, suggesting its role in the development of these rare tumors. This finding provides insight into the molecular mechanisms of pancreatic cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Endocrine pancreatic tumors are rare with poorly understood molecular drivers.
- The DPC4 gene, a tumor suppressor, is known to be inactivated in pancreatic adenocarcinoma.
Purpose of the Study:
- To investigate the role of the DPC4 gene in the tumorigenesis of pancreatic islet cell tumors.
- To screen for DPC4 mutations and deletions in various types of endocrine pancreatic tumors.
Main Methods:
- Mutation screening of DPC4's COOH-terminal domain (exons 8-11) using single-strand conformational variant (SSCP) analysis.
- Assessing DPC4 gene deletions via a PCR-based deletion assay.
- Analyzing 25 pancreatic islet cell tumors, including insulinomas, non-functioning carcinomas, gastrinomas, and vipomas.
Main Results:
- Alterations in the DPC4 gene were identified in 55% (5 of 9) of non-functioning endocrine pancreatic carcinomas.
- These alterations included point mutations, small intragenic deletions, and homozygous deletions of DPC4.
- No DPC4 alterations were found in insulinomas, gastrinomas, or vipomas.
Conclusions:
- The DPC4 gene is a significant target in the tumorigenesis of non-functioning neuroendocrine pancreatic carcinomas.
- DPC4 inactivation appears specific to non-functioning subtypes, differentiating them from other endocrine pancreatic tumors.