Gastroenterology

Gastroenterology

Volume 142, Issue 4, April 2012, Pages 855-864.e8
Gastroenterology

Original Research
Basic and Translational—Alimentary Tract
Field Cancerization in the Intestinal Epithelium of Patients With Crohn's Ileocolitis

https://doi.org/10.1053/j.gastro.2011.12.004Get rights and content

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.

Section snippets

Patients and Methods

See Supplementary Materials and Methods for full methods.

Results

Somatic mutations in TP53, CDKN2A, or KRAS were detected in neoplastic tissue from 7 of 10 patients (Table 1). Individual histologically normal, inflamed, or dysplastic crypts, cancer glands, or small areas of poorly differentiated tumor (∼500 cells) were then microdissected from multiple tissue samples from each patient with detected mutations and genotyped for the somatic mutation(s) detected in the patient’s neoplasia (Supplementary Table 3).

Discussion

The genetic and histologic mechanisms driving the development of CD-associated cancers have not been conclusively determined. The data presented herein are strong evidence that field cancerization, the replacement of the normal epithelium with a protumorigenic clone,8, 9 before any dysplastic histologic change contributes to carcinogenesis in patients with CD. In 5 of 7 informative patients with neoplasia, the same point mutation in KRAS, CDKN2A, or TP53 could be detected within the tumor,

Acknowledgments

Trevor A. Graham's present address is: Center for Evolution and Cancer, University of California, San Francisco, 2340 Sutter Street, Box 1351, San Francisco, California 94143.

The authors thank members of the Equipment Park and Experimental Histopathology Laboratories at the Cancer Research UK London Research Institute for technical assistance.

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    Conflicts of interest The authors disclose no conflicts.

    Funding S.G. received funding from the Price Institute of Surgical Research, University of Louisville, and Sarah Shallenberger Brown and support in part from National Institutes of Health/National Institute of Environmental Health Sciences grant 1P30ES014443-01A1. T.A.G., R.J., S.J.L., and N.A.W. were supported by Cancer Research UK. M.R.-J. is supported by UCLH/UCL Comprehensive Biomedical Research Centre. T.A.G. and M.R.-J. received funding for this study from the University College London Hospitals Charities - Fast Track Grant.

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