title: Utility of molecular genetic signatures in the delineation of gastric neoplasia.
abstract: BACKGROUND
  Current techniques to define gastric neoplasia are limited but molecular genetic signatures can categorize tumors and provide biological rationale for predicting clinical behavior. We identified three gene signatures: Chromogranin A (CgA), MAGE-D2 (adhesion), and MTA1 (metastasis) that define gastrointestinal (GI) carcinoids and hypothesize that their expression can delineate gastric neoplasia. This strategy provides a molecular basis to define neuroendocrine gastric carcinoids (GCs), neuronal stromal tumors (GISTs), or epithelial cell (gastric adenocarcinomas [GCAs])-derived tumors.
  
  
  METHODS
  Total RNA was isolated from 38 GCs: Type I/II (n = 7), Type III/IV (n = 6), GISTs (n = 12), GCAs (n = 13), and normal mucosa (n = 12). Quantitative reverse transcriptase polymerase chain reaction (Q RT-PCR) gene expression was quantified against glyseraldehyde-3-phosphate dehydrogenase (GAPDH) and CgA and MTA1 protein expression levels were analyzed by immunohistochemical analyses of a gastric neoplasia microarray.
  
  
  RESULTS
  CgA was elevated in Type I/II (10-fold; P < .01) and Type III/IV (100-fold, P < .005), decreased in GISTs (100-fold, P < .03), and unchanged in GCAs. MAGE-D2 was 5-10-fold elevated (P < .05) in Type III/IV, GISTs, and GCAs but not in Type I/II tumors. MTA1 (> 5-fold, P < .01) was elevated in GCs (Type III/IV>I/II, P < .05), in GISTs (> 4-fold, P < .05), and GCAs. CgA protein levels were elevated in GCs (P < .005) but not in GISTs and GCAs. MTA1 levels were elevated in all tumors (P < .02) compared with normal, and especially with tumor invasion (P < .05).
  
  
  CONCLUSIONS
  CgA discriminates GCs from other gastric neoplasms; overexpression of MAGE-D2 and MTA1 differentiate Type III/IV from Type I/II GCs. GISTs share similar expression patterns with Type III/IV GCs but have decreased CgA. MTA1 is a marker of tumor invasion.
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kidd
authors.forename: Irvin M
authors.initials: IM
authors.lastname: Modlin
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.forename: Robert L
authors.initials: RL
authors.lastname: Camp
authors.forename: Geeta N
authors.initials: GN
authors.lastname: Eick
authors.forename: Igor
authors.initials: I
authors.lastname: Latich
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Zikusoka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics*; D002276:Carcinoid Tumor / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D053379:Chromogranin A; D002864:Chromogranins / Q000096:biosynthesis / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D015534:Trans-Activators
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; D053379:Chromogranin A; D002864:Chromogranins; D005819:Genetic Markers; C451414:MAGED2 protein, human; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D006655:Histone Deacetylases