title: Aberrant crypt foci as precursors of the dysplasia-carcinoma sequence in patients with ulcerative colitis.
abstract: OBJECTIVE
  Long-standing ulcerative colitis (UC) predisposes patients to the development of colorectal cancer, but surveillance of colitis-associated cancer by detecting the precancerous lesion dysplasia is often difficult because of its rare occurrence and normal-looking appearance. In sporadic colorectal cancer, aberrant crypt foci (ACF) have been reported by many investigators to be precursor lesions of the adenoma-carcinoma sequence. In the present study, we analyzed the genetic background of ACF to determine whether they could be precursors for dysplasia, and we examined the usefulness of endoscopic examination of ACF as a surrogate marker for surveillance of colitis-associated cancer.
  
  
  METHODS
  ACF were examined in 28 UC patients (19 patients with UC alone and 9 patients with UC and dysplasia; 2 of those patients with dysplasia also had cancer) using magnifying endoscopy. K-ras, APC, and p53 mutations were analyzed by two-step PCR RFLP, in vitro--synthesized protein assay, and single-strand conformation polymorphism, respectively. Methylation of p16 was analyzed by methylation-specific PCR.
  
  
  RESULTS
  ACF that appeared distinct endoscopically and histologically were identified in 27 out of 28 UC patients. They were negative for K-ras, APC, and p53 mutations but were frequently positive for p16 methylation (8 of 11; 73%). In dysplasia, K-ras and APC mutations were negative but p53 mutation (3 of 5; 60%) and p16 methylation (3 of 5; 60%) were positive. There was a significant stepwise increase in the number of ACF from patients with UC alone to patients with dysplasia and to patients with cancer. Univariate and multivariate analyses showed significant correlations between ACF and dysplasia.
  
  
  CONCLUSIONS
  We have disclosed an ACF-dysplasia-cancer sequence in colitis-associated carcinogenesis similar to the ACF-adenoma-carcinoma sequence in sporadic colon carcinogenesis. This study suggests the use of ACF instead of dysplasia for the surveillance of colitis cancer and warrants further evaluation of ACF as a surveillance marker in large-scale studies.
authors.affiliation: Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kukitsu
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Takayama
authors.forename: Koji
authors.initials: K
authors.lastname: Miyanishi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nobuoka
authors.forename: Shinichi
authors.initials: S
authors.lastname: Katsuki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sato
authors.forename: Rishu
authors.initials: R
authors.lastname: Takimoto
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Junji
authors.initials: J
authors.lastname: Kato
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sonoda
authors.forename: Sumio
authors.initials: S
authors.lastname: Sakamaki
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Niitsu
mesh_terms: D000328:Adult; D003093:Colitis, Ulcerative / Q000235:genetics / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D016099:Endoscopy, Gastrointestinal; D005260:Female; D017491:Genes, APC; D019942:Genes, p16; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008297:Male; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction