Field Cancerization in the Intestinal Epithelium of Patients With Crohn's Ileocolitis

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 142; no. 4; pp. 855 - 864.e8
• Main Authors: Galandiuk, Susan, Rodriguez–Justo, Manuel, Jeffery, Rosemary, Nicholson, Anna M, Cheng, Yong, Oukrif, Dahmane, Elia, George, Leedham, Simon J, McDonald, Stuart A.C, Wright, Nicholas A, Graham, Trevor A
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2012
• Subjects: Adult; Aged; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Child; Clonal Ordering; Clone Cells - pathology; Colitis - complications; Colitis - genetics; Colitis - metabolism; Colitis - pathology; CRC; Crohn Disease - complications; Crohn Disease - genetics; Crohn Disease - metabolism; Crohn Disease - pathology; Cyclin-Dependent Kinase Inhibitor p16 - genetics; DNA Mutational Analysis; Gastroenterology and Hepatology; Genetic Predisposition to Disease; Humans; Ileitis - complications; Ileitis - genetics; Ileitis - metabolism; Ileitis - pathology; Immunohistochemistry; Inflammatory Bowel Disease; Intestinal Neoplasms - chemistry; Intestinal Neoplasms - genetics; Intestinal Neoplasms - pathology; Laser Capture Microdissection; Middle Aged; Oncogene; Phenotype; Point Mutation; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Time Factors; Tumor Progression; Tumor Suppressor Protein p53 - analysis; Tumor Suppressor Protein p53 - genetics; Clonal Ordering; CD; LOH; Oncogene; Tumor Progression; UC; CRC; ulcerative colitis; Inflammatory Bowel Disease; loss of heterozygosity; PCR; polymerase chain reaction; Crohn’s disease
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2011.12.004

Background & Aims 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.