title: Field cancerization in the intestinal epithelium of patients with Crohn's ileocolitis.
abstract: OBJECTIVE
  Tumors that develop in patients with Crohn's disease tend be multifocal, so field cancerization (the replacement of normal cells with nondysplastic but tumorigenic clones) might contribute to intestinal carcinogenesis. We investigated patterns of tumor development from pretumor intestinal cell clones.
  
  
  METHODS
  We performed genetic analyses of multiple areas of intestine from 10 patients with Crohn's disease and intestinal neoplasia. Two patients had multifocal neoplasia; longitudinal sections were collected from 3 patients. Individual crypts were microdissected and genotyped; clonal dependency analysis was used to determine the order and timing of mutations that led to tumor development.
  
  
  RESULTS
  The same mutations in KRAS, CDKN2A(p16), and TP53 that were observed in neoplasias were also present in nontumor, nondysplastic, and dysplastic epithelium. In 2 patients, carcinogenic mutations were detected in nontumor epithelium 4 years before tumors developed. The same mutation (TP53 p.R248W) was detected at multiple sites along the entire length of the colon from 1 patient; it was the apparent founder mutation for synchronous tumors and multiple dysplastic areas. Disruption of TP53, CDKN2A, and KRAS were all seen as possible initial events in tumorigenesis; the sequence of mutations (the tumor development pathway) differed among lesions.
  
  
  CONCLUSIONS
  Pretumor clones can grow extensively in the intestinal epithelium of patients with Crohn's disease. Segmental resections for neoplasia in patients with Crohn's disease might therefore leave residual pretumor disease, and dysplasia might be an unreliable biomarker for cancer risk. Characterization of the behavior of pretumor clones might be used to predict the development of intestinal neoplasia.
authors.affiliation: Histopathology Laboratory, Cancer Research UK London Research Institute, London, England. s0gala01@louisville.edu
authors.forename: Susan
authors.initials: S
authors.lastname: Galandiuk
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.forename: Rosemary
authors.initials: R
authors.lastname: Jeffery
authors.forename: Anna M
authors.initials: AM
authors.lastname: Nicholson
authors.forename: Yong
authors.initials: Y
authors.lastname: Cheng
authors.forename: Dahmane
authors.initials: D
authors.lastname: Oukrif
authors.forename: George
authors.initials: G
authors.lastname: Elia
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Leedham
authors.forename: Stuart A C
authors.initials: SA
authors.lastname: McDonald
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Graham
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002648:Child; D002999:Clone Cells / Q000473:pathology; D003092:Colitis / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D006801:Humans; D007079:Ileitis / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D061346:Laser Capture Microdissection; D008875:Middle Aged; D010641:Phenotype; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins