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Field cancerization in the intestinal epithelium of patients with Crohn's ileocolitis.

ABSTRACT: 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.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.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.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.

SUBMITTER: Galandiuk S

PROVIDER: S-EPMC4446968 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Field cancerization in the intestinal epithelium of patients with Crohn's ileocolitis.

Galandiuk Susan S Rodriguez-Justo Manuel M Jeffery Rosemary R Nicholson Anna M AM Cheng Yong Y Oukrif Dahmane D Elia George G Leedham Simon J SJ McDonald Stuart A C SA Wright Nicholas A NA Graham Trevor A TA

Gastroenterology 20111213 4

<h4>Background & aims</h4>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.<h4>Methods</h4>We performed genetic analyses of multiple areas of intestine from 10 patients with Crohn's disease and intestinal neoplasia. Two patients had multifocal neo ...[more]

PMID: 22178590

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Project description:The potential involvement of type 2 diabetes mellitus (T2DM) as a risk factor for colon cancer (CC) has been previously reported. While several clinical studies show a higher incidence of CC and a lower survival rate in diabetics, others report no association. Our own experience indicates that diabetes does not seem to worsen the prognosis once the tumor is present. Despite this controversy, there are no wide-spectrum molecular studies that delve into the impact of T2DM-related mechanisms in colon carcinogenesis. Here, we present a transcriptomic and proteomic profiling of paired tumor and normal colon mucosa samples in a cohort of 42 CC patients, 23 of which have T2DM. We used gene set enrichment and network approaches to extract relevant pathways in diabetics, referenced them to current knowledge, and tested them using in vitro techniques. Through our transcriptomics approach, we identified an unexpected overlap of pathways overrepresented in diabetics compared to nondiabetics, in both tumor and normal mucosa, including diabetes-related metabolic and signaling processes. Proteomic approaches highlighted several cancer-related signaling routes in diabetics found only in normal mucosa, not in tumors. An integration of the transcriptome and proteome analyses suggested the deregulation of key pathways related to colon carcinogenesis which converged on tumor initiation axis TEAD/YAP-TAZ as a potential initiator of the process. In vitro studies confirmed upregulation of this pathway in nontumor colon cells under high-glucose conditions. In conclusion, T2DM associates with deregulation of cancer-related processes in normal colon mucosa adjacent to tissue which has undergone a malignant transformation. These data support that in diabetic patients, the local microenvironment in normal colon mucosa may be a factor driving field cancerization promoting carcinogenesis. Our results set a new framework to study links between diabetes and colon cancer, including a new role of the TEAD/YAP-TAZ complex as a potential driver.

Project description:Field cancerization (FC) occurs in various epithelial carcinomas, including colorectal cancer, which indicates that the molecular events in carcinogenesis might occur in normal tissues extending from tumors. However, the transcriptomic characteristics of FC in colorectal cancer (CRC) remain largely unexplored. To investigate the changes in gene expression associated with proximity to the tumor, we analyzed the global gene expression profiles of cancer tissues and histologically normal tissues taken at various distances from the tumor (1 cm, 5 cm and the proximal end of the resected sample) from 32 rectal cancer patients. Significantly differentially expressed genes related to the distance from the tumor were screened by linear mixed effects analysis using the lme4 package in R. The distance-related differentially expressed genes that were gradually up-regulated (n=302) or gradually down-regulated (n=568) from normal tissues to the tumor were used to construct protein-protein interaction (PPI) networks. Three subnetworks among the gradually up-regulated genes and four subnetworks among the gradually down-regulated genes were identified using the MCODE plugin in the Cytoscape software program. The most significantly enriched Gene Ontology (GO) biological process terms were "ribosome biogenesis", "mRNA splicing via spliceosome", and "positive regulation of leukocyte migration" for the gradually up-regulated subnetworks and "cellular calcium ion homeostasis", "cell separation after cytokinesis", "cell junction assembly", and "fatty acid metabolic process" for the gradually down-regulated subnetworks. Combined with the previously constructed multistep carcinogenesis model used for the analysis, 50.59% of the genes in the subnetworks (43/85) displayed identical changes in expression from normal colon tissues to adenoma and colon cancer. We focused on the 7 genes associated with fatty acid metabolic processes in the distance-related down-regulated subnetwork. Survival analysis of patients in the CRC dataset from The Cancer Genome Atlas (TCGA) revealed that higher expression of these 7 genes, especially CPT2, ACAA2 and ACADM, was associated with better prognosis (p = 0.034, p = 0.00058, p = 0.039, p = 0.04). Cox proportional hazards regression analysis revealed that CPT2 was an independent prognostic factor (p = 0.004131). Our results demonstrate that field cancerization occurs in CRC and affects gene expression in normal tissues extending from the tumor, which may provide new insights into CRC oncogenesis and patient progression.

Dataset Information

Field cancerization in the intestinal epithelium of patients with Crohn's ileocolitis.

Publications

Field cancerization in the intestinal epithelium of patients with Crohn's ileocolitis.

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