Inactivation of differential tumor suppressor genes in gastro-entero-pancreatic neuroendocrine tumors

Introduction: Little is known about the mechanisms contributing to the molecular pathogenesis of neuroendocrine tumors of the gastro-entero-pancreatic system (GEP-NET). We recently demonstrated the role of promoter methylation of certain tumor suppressor genes in GEP-NET. In this study we investigated the differential inactivation of tumor suppressor genes and the functional significance of genes silenced by promoter methylation which are believed to be frequently inactivated in GEP-NET of different origins.

Methods: In this study 118 mainly well differentiated fore- and midgut GEP-NET from 71 patients were investigated. The methylation status of the hMLH1, p16, APC, O⁶-MGMT, PTEN, HIC1, e -cadherin. RASSF1a, TIMP3 and MEN1-genes was examined by methylation specific PCR. The expression profile of p16 and APC was investigated by immunohistochemistry.

Results: Promoter hypermethylation was a prominent feature of GEP-NET from different sites and origins. Apart from a significant difference in promoter hypermethylation of the runx3-gene in functional versus non-functional GEP-NET (p=0,023), there was no difference in the promoter methylation profile of the remaining tumors. However, we found a significant loss of p16-expression (p=0,026) in insulinoma vs. pancreatic non-functional and non-functional GEP-NET. p16-expression in functional vs. non-functional GEP-NET was also significantly decreased (p=0,05). APC was expressed significantly less in gastrinoma (p=0,01) and functional GEP-NET (p=0,01) vs. non-functional tumors. APC-expression was also strongly decreased in insulinoma vs. pancreatic non-functional tumors (p=0,017).

Discussion: This is the first study demonstrating a significant difference in the expression of the tumor suppressor genes p16 and APC in GEP-NET. In general, functional GEP-NET of the pancreas showed a decreased expression of both tumor suppressor genes. Promoter methylation was a common feature in all tumor types from various origins with only few differences. Further studies are ongoing to investigate the biological significance of our findings and to correlate tumor differentiation to genes and mechanisms of the molecular pathogenesis of GEP-NET

Keywords: GEP-NET, promoter methylation, tumor suppressor genes