{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T08:36:56Z","timestamp":1791103016470,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2007,2,2]],"date-time":"2007-02-02T00:00:00Z","timestamp":1170374400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2007,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Little is known about the molecular pathogenesis of neuroendocrine tumors (NET) of the gastro\u2010entero\u2010pancreatic (GEP) system. We analyzed genetic and epigenetic alterations as well as the CpG island methylator phenotype (CIMP). The study comprised 118 well\u2010differentiated fore\u2010 and mid\u2010gut GEP\u2010NET from 71 patients. In addition to loss of heterozygosity (LOH), microsatellite instability (MSI) and the methylation status of various tumor associated genes were examined. The expression profile of p16, APC and MENIN was investigated by immunohistochemistry. None of the tumors was highly microsatellite unstable, LOH was found in 22.2%. Significant differences in promoter hypermethylation were identified in the <jats:italic>RUNX3<\/jats:italic> and the <jats:italic>O<\/jats:italic><jats:sup>6<\/jats:sup>\u2010<jats:italic>MGMT<\/jats:italic> genes. We found a significant loss of p16 expression in insulinomas (<jats:italic>p<\/jats:italic> = 0.05) and functional NET (<jats:italic>p<\/jats:italic> = 0.01), respectively. APC was expressed less in gastrinomas (<jats:italic>p<\/jats:italic> = 0.01) and functional GEP\u2010NET (<jats:italic>p<\/jats:italic> = 0.05) <jats:italic>vs.<\/jats:italic> nonfunctional tumors. MENIN expression was reduced in pancreatic <jats:italic>vs<\/jats:italic>. extrapancreatic NET (<jats:italic>p<\/jats:italic> = 0.008) and in insulinomas <jats:italic>vs.<\/jats:italic> nonfunctional GEP\u2010NET (<jats:italic>p<\/jats:italic> = 0.019) and NET associated with the carcinoid syndrome (<jats:italic>p<\/jats:italic> = 0.029). Further CIMP and a Ki\u201067 index &gt;10% showed a close correlation. Outcome analysis of 19 patients showed a better survival for CIMP\u2010negative patients. The analyses identified significant genetic and epigenetic alterations in well\u2010differentiated fore\u2010 and mid\u2010gut NET. CIMP, similar to Ki\u201067, might turn out to be of prognostic relevance. \u00a9 2007 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.22569","type":"journal-article","created":{"date-parts":[[2007,2,3]],"date-time":"2007-02-03T09:25:57Z","timestamp":1170494757000},"page":"2157-2164","source":"Crossref","is-referenced-by-count":83,"title":["Analysis of molecular pathways in sporadic neuroendocrine tumors of the gastro\u2010entero\u2010pancreatic system"],"prefix":"10.1002","volume":"120","author":[{"given":"Christian 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