title: Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis.
abstract: 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-beta 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.
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Cancer Center, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Duerr
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mizukami
authors.forename: Aylwin
authors.initials: A
authors.lastname: Ng
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Warshaw
authors.forename: Jonathan
authors.initials: J
authors.lastname: Glickman
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Kulke
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000145:classification / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D012334:RNA, Neoplasm