title: Epithelial and stromal genetic instability linked to tumor suppressor genes in ulcerative colitis-associated tumorigenesis.
abstract: OBJECTIVE
  We have previously documented not only epithelial but also stromal genetic instability in ulcerative colitis (UC)-associated lesions, including adenocarcinomas, using microsatellite markers close to the p53 gene on chromosome 17 (Chr.17). However, about half of the UC-associated tumors do not have p53 gene alterations. The purpose of this study was to detect early genetic instability (loss of heterozygosity (LOH) and microsatellite instability (MSI)) of both epithelial and stromal cells in UC-associated tumorigenesis, using different microsatellite markers from the p53 gene.
  
  
  METHODS
  The laser-captured microdissection-PCR-GeneScan method was applied to investigate genetic instability in both the epithelial and stromal elements of early UC-associated lesions (regenerative mucosa and dysplasia) and carcinomas using multiple microsatellite markers, chiefly close to tumor suppressor genes (TSGs: p16(INK4A), Rb, Smad4 and fragile histidine triad (FHIT)). Furthermore, expression of their gene products was analyzed by immunohistochemistry.
  
  
  RESULTS
  In epithelium, although LOH for Chr.17 markers increased along with histological progression, the frequencies of LOH or MSI for TSG markers were found to be almost constantly increased in both stromal and epithelial components of all lesion types. In contrast, genetic instability of National Cancer Institute (NCI)-recommended standard markers was not found to be significantly correlated with UC-associated tumorigenesis. Immunohistochemically, epithelial p16(INK4A) expression tended to be decreased in LOH-positive lesions (p = 0.0780) and Smad4 expression was significantly decreased (p < 0.05).
  
  
  CONCLUSIONS
  These results suggest that genetic instability in the stroma, especially regarding TSG markers, may play an important role in early-phase, UC-associated tumorigenesis. In addition, decreased expression of TSG due to genetic alteration might contribute to tumorigenesis.
authors.affiliation: Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yagishita
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshida
authors.forename: Kayo
authors.initials: K
authors.lastname: Ishiguro
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Numata
authors.forename: Isao
authors.initials: I
authors.lastname: Okayasu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D043171:Chromosomal Instability; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged