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Claudin-4, Mitogen-Activated Protein Kinase Kinase 4, and Stratifin Are Markers of Gastric Adenocarcinoma Precursor Lesions

Departments of ¹ Oncology, ² Pathology, and ³ Surgery, and ⁴ Curriculum in Medicine, The Johns Hopkins University School of Medicine; ⁵ Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health; ⁶ Department of Surgery, University of Maryland Medical System, Baltimore, Maryland; and ⁷ The Academic Medical Center, Amsterdam, the Netherlands

Requests for reprints: Elizabeth Montgomery, Department of Pathology, Johns Hopkins Hospital, Weinberg 2442, 401 North Broadway, Baltimore MD 21231. Phone: 410-614-2308; Fax: 443-287-3818. E-mail: emontgom{at}jhmi.edu

Approximately 23,000 new gastric cancer cases and 12,000 associated deaths occur annually in the United States. Intestinal metaplasia and gastric epithelial dysplasia are precursor lesions to gastric adenocarcinoma, but are not readily detectable clinically, radiographically, or endoscopically. A noninvasive method of precursor detection would require the ability to distinguish precursor lesions from adjacent normal mucosa. In search of such markers, tissue microarrays were prepared for 133 patients of resected gastric adenocarcinoma. Tissue microarrays contained primary cancer, normal stomach, intestinal metaplasia, and gastric epithelial dysplasia and were probed with antibodies against nine potential markers that were either identified in a database of genes overexpressed in gastric adenocarcinoma or were already of interest to our laboratory: claudin-4, mitogen-activated protein kinase kinase 4 (MKK4), 14-3-3 (stratifin), S100A4, mesothelin, fascin, topoisomerase II, HER-2/neu, and epithelial growth factor receptor. Three markers discriminated gastric adenocarcinoma precursor lesions from normal gastric mucosa. Claudin-4 expression was present in 36 intestinal metaplasia lesions (100%) and 14 gastric epithelial dysplasia lesions (100%), but in only 16 normal stomach samples (15%). MKK4 expression was present in 24 intestinal metaplasia lesions (89%) and 12 gastric epithelial dysplasia lesions (100%), but in only 6 normal stomach samples (8%). Stratifin expression was present in 29 intestinal metaplasia lesions (97%) and 8 gastric epithelial dysplasia lesions (100%), but in only 2 normal stomach samples (3%). Sensitivity and specificity for detection of the precursor lesion intestinal metaplasia were 100% and 85%, respectively, for claudin-4; 89% and 92%, respectively, for MKK4; and 97% and 97%, respectively, for stratifin. In primary cancers, 123 of 125 (98.4%) were positive for claudin-4, 116 of 126 (94%) for MKK4, and 111 of 120 (92%) for stratifin. In conclusion, claudin-4, MKK4, and stratifin immunolabeling detects precursor lesions of gastric adenocarcinoma that are otherwise clinically, radiographically, and endoscopically inapparent. These findings may prove useful in the diagnosis and therapeutic targeting of gastric adenocarcinoma precursor lesions. (Cancer Epidemiol Biomarkers Prev 2006;15(2):281–7)

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