title: Gastric and intestinal phenotypic marker expression in early differentiated-type tumors of the stomach: clinicopathologic significance and genetic background.
abstract: OBJECTIVE
  Gastric and intestinal phenotypic cell markers are expressed in gastric carcinomas, irrespective of their histologic type. In the present study, we determined the clinicopathologic significance of phenotypic marker expression in early-stage gastric differentiated-type tumors and the association between marker expression and genetic alterations.
  
  
  METHODS
  Phenotypic marker expression was determined by examining the expressions of human gastric mucin (HGM), MUC6, MUC2, and CD10 in 63 gastric adenomas, 133 early differentiated-type carcinomas, and 24 follow-up cases with gastric adenoma. Tumors were classified into gastric, gastric and intestinal mixed, or intestinal phenotypes according to the immunopositivity of the above markers. The presence of mutations in APC, K-ras, and p53 and the microsatellite instability status were also determined in all tumors.
  
  
  RESULTS
  The expressions of HGM and MUC6, representing gastric or gastric and intestinal mixed phenotypes, were significantly associated with high-grade atypia in the 63 gastric adenomas. Among the 133 early differentiated-type carcinomas, HGM expression was significantly associated with mixed-type (with an undifferentiated-type component) tumors and lymph node metastasis. MUC2 expression was inversely associated with submucosal invasion. A multivariate analysis revealed that gastric adenomas were significantly associated with the intestinal phenotype and were inversely associated with p53 mutation compared with early differentiated-type carcinomas. Among all 196 tumors, APC mutation was significantly associated with CD10 expression and the intestinal phenotype and was inversely associated with the expressions of HGM and MUC6. The microsatellite instability status was significantly associated with MUC6 expression. Malignant transformation from gastric adenoma to carcinoma was shown in 5 of the 24 follow-up cases of gastric adenoma. The malignant transformation was significantly associated with the gastric and intestinal mixed phenotype and was inversely associated with APC mutation. No malignant transformation was found in intestinal phenotype gastric adenomas with APC mutation.
  
  
  CONCLUSIONS
  Our present findings show that phenotypic marker expression is associated with tumor aggressiveness during the early stage of gastric differentiated-type tumors. Differences in the biological behavior of tumors with different phenotypes may result from differences in the genetic backgrounds during the incipient phase of gastric tumorigenesis.
authors.affiliation: Division of General and Gastroenterological Surgery, Department of Surgery and Clinical Research Laboratory, Showa University School of Medicine, Tokyo, Japan. surgery@med.showa-u.ac.jp
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tajima
authors.forename: Kimiyasu
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Reiko
authors.initials: R
authors.lastname: Makino
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Nishino
authors.forename: Shigeo
authors.initials: S
authors.lastname: Aoki
authors.forename: Masanori
authors.initials: M
authors.lastname: Kato
authors.forename: Koji
authors.initials: K
authors.lastname: Morohara
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kaetsu
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kusano
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D004252:DNA Mutational Analysis; D005752:Gastric Mucins / Q000096:biosynthesis; D017491:Genes, APC; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D055262:Mucin-2; D055272:Mucin-6; D009077:Mucins / Q000096:biosynthesis; D009154:Mutation; D015260:Neprilysin / Q000096:biosynthesis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D005752:Gastric Mucins; C524625:MUC2 protein, human; C524734:MUC6 protein, human; D055262:Mucin-2; D055272:Mucin-6; D009077:Mucins; D015260:Neprilysin