Analysis of molecular pathways in sporadic neuroendocrine tumors of the gastro-entero-pancreatic system

Background & Aims: Little is known about the molecular pathogenesis of neuroendocrine tumors (NET) of the gastro-entero-pancreatic (GEP) system. We therefore analyzed genetic and epigenetic alterations as well as the CpG island methylator phenotype (CIMP) and the functional significance of genes silenced by promoter methylation in GEP-NET.

Methods: The study comprised 118 well-differentiated foregut and midgut GEP-NET from 71 patients. In addition to loss of heterozygosity (LOH), microsatellite instability (MSI) and the methylation status of the hMLH1, p16, APC, O6-MGMT, PTEN, HIC1, E-cadherin, RASSF1A, TIMP3, RUNX3 and MEN1 genes were examined. The expression profile of p16, APC and MENIN was investigated by immunohistochemistry.

Results: None of the tumors was highly microsatellite unstable. Overall, 22.2% of the tumors had LOH. Promoter hypermethylation was observed frequently. Significant differences in promoter hypermethylation were identified in the RUNX3 and the O6-MGMT genes. We found a significant loss of p16 expression in insulinomas (p=0.05) and in functional GEP-NET (p=0.01), respectively. APC was expressed significantly less in gastrinomas (p=0.01) and functional GEP-NET (p=0.05) vs. non-functional tumors. APC expression was also lower in insulinomas vs. pancreatic non-functional tumors (p=0.017). MENIN expression was reduced in pancreatic vs. extrapancreatic NET (p=0.008) and in insulinomas vs. non-functional GEP-NET (p=0.019) and NET associated with the carcinoid syndrome (p=0.021). Further CIMP and a Ki-67 index >10% showed a close correlation.

Conclusions: Taken together, the analyses identified significant genetic and epigenetic alterations in well-differentiated fore- and midgut NET. CIMP, similar to Ki-67, might turn out to be of prognostic relevance.