Aberrant Crypt Foci as Precursors of the Dysplasia-Carcinoma Sequence in Patients with Ulcerative Colitis

Abstract

Purpose: Long-standing ulcerative colitis (UC) predisposes patients to the development of colorectal cancer, but surveillance of colitis-associated cancer by detecting the precancerous lesion dysplasia is often difficult because of its rare occurrence and normal-looking appearance. In sporadic colorectal cancer, aberrant crypt foci (ACF) have been reported by many investigators to be precursor lesions of the adenoma-carcinoma sequence. In the present study, we analyzed the genetic background of ACF to determine whether they could be precursors for dysplasia, and we examined the usefulness of endoscopic examination of ACF as a surrogate marker for surveillance of colitis-associated cancer. Experimental Design: ACF were examined in 28 UC patients (19 patients with UC alone and 9 patients with UC and dysplasia; 2 of those patients with dysplasia also had cancer) using magnifying endoscopy. K-ras, APC, and p53 mutations were analyzed by two-step PCR RFLP, in vitro^synthesized protein assay, and single-strand conformation polymorphism, respectively. Methylation of p16 was analyzed by methylation-specific PCR. Results: ACF that appeared distinct endoscopically and histologically were identified in 27 out of 28 UC patients. They were negative for K-ras, APC, and p53 mutations but were frequently positive for p16 methylation (8 of 11; 73%). In dysplasia, K-ras and APC mutations were negative but p53 mutation (3 of 5; 60%) and p16 methylation (3 of 5; 60%) were positive. There was a significant stepwise increase in the number of ACF from patients with UC alone to patients with dysplasia and to patients with cancer. Univariate and multivariate analyses showed significant correlations between ACF and dysplasia. Conclusions: We have disclosed an ACF-dysplasia-cancer sequence in colitis-associated carcinogenesis similar to the ACF-adenoma-carcinoma sequence in sporadic colon carcinogenesis. This study suggests the use of ACF instead of dysplasia for the surveillance of colitis cancer and warrants further evaluation of ACF as a surveillance marker in large-scale studies.It is commonly recognized that long-standing ulcerative colitis (UC) predisposes patients to the development of colorectal cancer (1). However, the detection of early colorectal cancer is often difficult in patients with UC because there is inflammation in the background mucosa and it predominantly represents flat-type ill-delineated lesions (2, 3). Therefore, colitis-associated cancer is often detected at an advanced stage and is characterized by a very poor prognosis. One approach to overcome this difficulty is to use dysplasia, which is considered to be a precancerous lesion in colitis-associated cancer, as a surrogate marker for early detection of colitis-associated cancer (4, 5). However, identification of dysplasia by endoscopy requires greater skill than detection of cancer itself because of its rare occurrence and apparently normal-looking appearance (6).We previously succeeded in identifying aberrant crypt foci (ACF) in non-UC subjects using ...

Sporadic Aberrant Crypt Foci Are Not a Surrogate Endpoint for Colorectal Adenoma Prevention

“…There were significant correlations between the number of ACF, the presence of dysplastic ACF, ACF size, and the number of adenomas, as well as the provocative findings of a reduction in ACF in a substudy of the effects of a nonsteroidal anti-inflammatory drug that are discussed later. Stimulated by this Japanese study, investigations of ACF and their potential use as a surrogate endpoint of clinical prevention trials proceeded rapidly (17)(18)(19)(20).…”

Carcinogenesis in Ulcerative Colitis

“…These results are consistent with the hypothesis that age-related methylation marks (and may lead to) the field defect that reflects acquired predisposition to colorectal neoplasia. More recently, Kukitsu et al (Kukitsu et al, 2008) identified hypermethylation and subsequent reduced p16 gene expression in aberrant crypt foci (ACF) in UC. These are the earliest detectable lesions in the CACRC pathway and suggest that aberrant methylation of tumour suppressor genes may also be an early event in CACRC carcinogenesis 3. Who, when and how to screen?…”

Inflammatory Bowel Disease and Colon Cancer

“…These results are consistent with the hypothesis that age-related methylation marks (and may lead to) the field defect that reflects acquired predisposition to colorectal neoplasia. More recently, Kukitsu et al (2008) identified hypermethylation and subsequently reduced p16 gene expression in aberrant crypt foci (ACF) in UC. These are the earliest detectable lesions in the CACRC pathway and suggest that aberrant methylation of tumour suppressor genes may be an early event in CACRC carcinogenesis.…”