Clonality, Founder Mutations, and Field Cancerization in Human Ulcerative Colitis–Associated Neoplasia

doi:10.1053/j.gastro.2008.10.086

Gastroenterology

Volume 136, Issue 2, February 2009, Pages 542-550.e6

https://doi.org/10.1053/j.gastro.2008.10.086 Get rights and content

Background & Aims

The clonality of colitis-associated neoplasia has not been fully determined. One previous report showed polyclonal origins with subsequent monoclonal outgrowth. We aimed to assess the clonality and mutation burden of individual crypts in colitis-associated neoplasias to try to identify gatekeeping founder mutations, and explore the clonality of synchronous lesions to look for field effects.

Methods

Individual crypts (range, 8–21 crypts) were microdissected from across 17 lesions from 10 patients. Individual crypt adenomatous polyposis coli (APC), p53, K-RAS, and 17p loss of heterozygosity mutation burden was established using polymerase chain reaction and sequencing analysis. Serial sections underwent immunostaining for p53, β-catenin, and image cytometry to detect aneuploidy.

Results

In most lesions an oncogenic mutation could be identified in all crypts across the lesion showing monoclonality. This founder mutation was a p53 lesion in the majority of neoplasms but 4 tumors had an initiating K-RAS mutation. Some nondysplastic crypts surrounding areas of dysplasia were found to contain clonal p53 mutations and in one case 3 clonal tumors arose from a patch of nondysplastic crypts containing a K-RAS mutation.

Conclusions

This study used mutation burden analysis of individual crypts across colitis-associated neoplasms to show lesion monoclonality. This study confirmed p53 mutation as initiating mutation in the majority of lesions, but also identified K-RAS activation as an alternative gatekeeping mutation. Local and segmental field cancerization was found by showing pro-oncogenic mutations in nondysplastic crypts surrounding neoplasms, although field changes are unlikely to involve the entire colon because widely separated tumors were genetically distinct.

Section snippets

Tissue and Slides

Seventeen paraffin-embedded blocks of UC dysplasia, cancer arising from dysplasia or colitis-associated cancer, were obtained from the pathology libraries of Leicester General Hospital and University College London Hospital. The blocks were taken from the colectomy specimens of 10 patients; 3 patients had multiple lesions (Table 1, patients 8–10). Ethical approval was obtained from the Multicentre Research Ethics Committee (07/Q1604/17). Serial 5-μm sections were cut. Sections 1–3 and 5–7 were

Results

The obtained tissue was divided on a histologic basis using H&E slides into dysplasia alone (6 blocks), carcinoma apparently arising from dysplasia (5 blocks), and carcinoma alone (6 blocks).

Discussion

The clonality of colitis-associated dysplasia has not been fully explored. In all but one of the informative lesions analyzed here an established tumor-suppressor or oncogene mutation could be identified and in each case was present in every dissected crypt from across the plaque (fixation of mutation within the tissue), suggesting monoclonality. This monoclonality was seen in all lesions, from small low-grade dysplastic plaques through early malignancies arising from dysplastic precursor

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: The authors disclose the following: Funded by the Medical Research Council (S.J.L.), by Cancer Research UK (S.J.L. and N.A.W.); and by Oxford University (S.A.C.M. and J.A.Z.J.).

View full text

Basic—Alimentary TractClonality, Founder Mutations, and Field Cancerization in Human Ulcerative Colitis–Associated Neoplasia

Background & Aims

Methods

Results

Conclusions

Section snippets

Tissue and Slides

Results

Discussion

Gastroenterology

Gastroenterology

Am J Pathol

Gastroenterology

Gastroenterology

Gastroenterology

Hum Pathol

Gastroenterology

The risk of colorectal cancer in ulcerative colitis: a meta-analysis

Gut

Inflammation and cancer IVColorectal cancer in inflammatory bowel disease: the role of inflammation

Am J Physiol Gastrointest Liver Physiol

Genetic alterations during colorectal-tumor development

N Engl J Med

Genetics of inflammatory bowel disease and associated cancers

Curr Colorectal Cancer Rep

Diagnostic value of DNA image cytometry in ulcerative colitis

Dig Dis Sci

DNA aneuploidy and histologic dysplasia in long-standing ulcerative colitisA 10-year follow-up study

Dis Colon Rectum

Basic—Alimentary Tract
Clonality, Founder Mutations, and Field Cancerization in Human Ulcerative Colitis–Associated Neoplasia