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¹ Gastrointestinal Unit, ² Department of Medicine, ³ Cancer Center, ⁴ Center for Computational and Integrative Biology, ⁵ Department of Pathology and ⁶ Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA⁷ Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02114, USA⁸ Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02114, USA

(Correspondence should be addressed to D C Chung, GI Unit, GRJ 825, Massachusetts General Hospital, 50 Blossom Street, Boston, Massachusetts 02114, USA; Email: dchung{at}partners.org)

Current classifications of human gastroenteropancreatic neuroendocrine tumors (NETs) are inconsistent and based upon histopathologic but not molecular features. We sought to compare a molecular classification with the World Health Organization (WHO) histologic classification, identify genes that may be important for tumor progression, and determine whether gastrointestinal NETs (GI-NETs) differ in their molecular profile from pancreatic NETs (PNETs). DNA microarray analysis was performed to identify differentially expressed genes in PNETs and GI-NETs. Confirmation of expression levels was obtained by quantitative real-time PCR. Immunoblotting and mutational analysis were performed for selected genes. Hierarchical clustering of 19 PNETs revealed a ‘benign’ and ‘malignant’ cluster that corresponded well with the WHO categories of well-differentiated endocrine tumor (WDET) and well-differentiated endocrine carcinoma (WDEC) respectively. FEV, adenylate cyclase 2 (ADCY2), nuclear receptor subfamily 4, group A, member 2 (NR4A2), and growth arrest and DNA-damage-inducible, beta (GADD45b) were the most highly up-regulated genes in the malignant group of PNETs. Platelet-derived growth factor receptor (PDGFR) was expressed in both WDETs and WDECs, and phosphorylation of PDGFR-β was observed in 83% of all PNETs. Malignant ileal GI-NETs exhibited a distinctive gene expression profile, and extracellular matrix protein 1 (ECM), vesicular monoamine member 1 (VMAT1), galectin 4 (LGALS4), and RET Proto-oncogene (RET) were highly up-regulated genes. Gene expression profiles reflect the current WHO classification and can distinguish benign from malignant PNETs and also PNETs from GI-NETs. This suggests that molecular profiling may enhance tumor classification schemes. Potential gene targets have also been identified, and PDGFR and RET are candidates that may represent novel therapeutic targets.