Utility of molecular genetic signatures in the delineation of gastric neoplasia.
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.
Kidd
Mark
M
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA.
Modlin
Irvin M
IM
Mane
Shrikant M
SM
Camp
Robert L
RL
Eick
Geeta N
GN
Latich
Igor
I
Zikusoka
Michelle N
MN
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
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