Analysis of K-ras, APC, and β-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis

Takayama, Tetsuji; Ohi, Motoh; Hayashi, Tsuyoshi; Miyanishi, Koji; Nobuoka, Atsushi; Nakajima, Tomohiro; Satoh, Tsutomu; Takimoto, Rishu; Kato, Junji; Sakamaki, Sumio; Niitsu, Yoshiro

doi:10.1053/gast.2001.27203

Cited by 243 publications

(186 citation statements)

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“…In contrast, mutations were detected in 4 of 5 (80%) non-UC ACF specimens (Fig. 2), consistent with our previous reports and those of other laboratories (7,11,14,15). Thus, the frequency of K-ras mutations in colitis ACF was relatively low compared with that of non-UC ACF.…”

Section: Endoscopic and Histologic Features Of Dysplasia (A-c) Acfsupporting

confidence: 91%

“…After observation of the entire colorectum, the lower rectum from the middle Houston valve to the dentate line was washed with plenty of water, stained with 0.2% methylene blue, and again washed with sufficient water for identification of ACF. Biopsies were taken under magnifying endoscopy as described previously (7,11). In this particular study, to avoid laborious and lengthy procedures considering the future application of ACF as a surveillance marker, the observation of ACF was limited to the lower rectum on the basis of our previous report; the number of ACF in the lower rectum correlated with that in entire colorectum (7).…”

Section: Methodsmentioning

confidence: 99%

“…UC patients in remission underwent magnifying endoscopy, which was done as described previously (7,11). In order to improve the visualization of ACF (i.e., accurate evaluation of ACF number), plenty of polyethyleneglycol was administered before examination.…”

Section: Methodsmentioning

confidence: 99%

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

Kukitsu¹,

Takayama²,

Miyanishi³

et al. 2008

Clinical Cancer Research

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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 ...

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Section: Endoscopic and Histologic Features Of Dysplasia (A-c) Acfsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

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

Kukitsu¹,

Takayama²,

Miyanishi³

et al. 2008

Clinical Cancer Research

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“…Aberrant crypt foci (ACF) are the earliest neoplastic lesions identified microscopically in human colonic mucosa. 1,2 Multiple genetic alterations found in ACF, such as activation of protooncogenes, 3,4 inactivation of tumor-suppressor genes, 4 chromosomal instability 5 and microsatellite instability, 6,7 suggest that ACF are putative precursors of colorectal cancer. Methylation of CpG islands is a molecular alteration common in many cancers.…”

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confidence: 99%

CpG island methylation in aberrant crypt foci and cancers from the same patients

Luo

Chen

Pretlow

2005

Intl Journal of Cancer

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Aberrant methylation of CpG islands is a common alteration in human colon cancer. Methylation of only a limited number of loci has been studied in aberrant crypt foci (ACF), the earliest identified premalignant lesions in the colon, and in only a limited number of lesions from the same patients. Methylation-specific PCR was used to analyze 35 ACF, samples of normal crypts with the same number of crypts as were in each ACF and 22 cancers from the same patients. Aberrant methylation in cellular retinol-binding protein 1 (CRBP1), MINT31 or H-cadherin (CDH13) was identified in 19 of 35 (54%) ACF. Hypermethylation of CRBP1, MINT31 or CDH13 was more frequent (15 of 22, 68%) in cancers. DNA methylation of CRBP1, MINT31 or CDH13 was not correlated between cancers and ACF from the same patients. Aberrant methylation was not correlated with patient age, number of crypts in the ACF or cancer stage. These results suggest that hypermethylation in the promoter region of some genes is an independent event, occurs early in human colon tumorigenesis and may play an important role during the transformation and progression of some lesions to colon cancers. ' 2005 Wiley-Liss, Inc.Key words: premalignant lesion; epigenetic alteration; hypermethylation; colon cancer Colon cancer is a malignant disease that develops stepwise through pathologically defined stages of tumor progression. Aberrant crypt foci (ACF) are the earliest neoplastic lesions identified microscopically in human colonic mucosa. 1,2 Multiple genetic alterations found in ACF, such as activation of protooncogenes, 3,4 inactivation of tumor-suppressor genes, 4 chromosomal instability 5 and microsatellite instability, 6,7 suggest that ACF are putative precursors of colorectal cancer. Methylation of CpG islands is a molecular alteration common in many cancers. 8 DNA methylation at cytosines located 5 0 to guanosines of CpG dinucleotides in the promoter region inhibits the transcription of genes and causes loss of gene expression. 8 While there have been many studies on the methylation of single or multiple genes in colon cancers 9-13 or polyps, 9,14,15 only a few have looked at methylation in ACF. [16][17][18] CpG island methylator phenotype (CIMP), 9 in which multiple loci are methylated in the same lesion but not in the normal mucosa, has been identified as a novel pathway of colon tumorigenesis. While concordant CIMP was reported for small numbers of polyps and cancers in the same patients 9 and for colonic lesions in patients with hyperplastic polyposis, 15 a lack of concordant methylation was reported for multiple polyps in patients without cancer. 14 ACF studies to date have looked at only a limited number of different samples from the same patient, and none has looked at cancers in the same patients. In our study, altered DNA methylation of the cellular retinol-binding protein 1 (CRBP1), H-cadherin (CDH13) and MINT31 was evaluated in multiple ACF and cancers from the same patients. The frequency of DNA methylation for these 3 loci was lower in ACF than in cancers, ...

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“…Thus, it seems difficult to evaluate actual colon carcinogenicity of lowdose PhIP alone in animal experimental models, especially if relying on quantitative analysis of neoplasms. Interest has therefore centered on aberrant crypt foci (ACF) found in both rodents and humans, 26,27 which enable investigators to quantify colon carcinogenic potentials of carcinogens in medium-term experiments. PhIP is known to induce ACF in different strains of rats in a dosedependent manner, 28 but to a much lower degree than azoxymethane (AOM) 29 or dimethylhydrazine (DMH).…”

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confidence: 99%

Lack of large intestinal carcinogenicity of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine at low doses in rats initiated with azoxymethane

Doi

Wanibuchi

Salim

et al. 2005

Intl Journal of Cancer

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2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), an abundant food-derived heterocyclic amine (HCA), has attracted particular attention as a human colon carcinogen. Humans are in fact exposed to continuous low doses of HCAs during lifetime. Therefore, we focused on rat large intestinal carcinogenicity of PhIP at levels that mimic practical human exposure. A total of 192 6-weekold male F344 rats were subcutaneously injected twice with 15 mg/ kg body weight azoxymethane (AOM), then continuously fed various doses (0, 0.001, 0.01, 0.1, 1, 10, 50 and 200 ppm) of PhIP in the diet. At week 16, aberrant crypt foci (ACF) were quantitatively analyzed. At week 36, tumor occurrence was pathologically analyzed. Then immunohistochemical examinations were performed. PhIP was found to enhance strongly AOM-initiated rat large intestinal tumorigenesis at high doses (50 and 200 ppm), while lower doses (0.001-10 ppm) had no apparent effects. High doses also caused variation in tumor histologic types and their distribution throughout the large intestinal segments. Frequencies of ACF/cm 2 did not meaningfully vary between the groups. Cellular proliferation activity in normal-appearing colonic mucosa was significantly increased at high doses. These novel findings may provide evidence of a low-dose potential for PhIP, with a no-observed effect level speculated to be 10 ppm in the present initiation-promotion experimental model. ' 2005 Wiley-Liss, Inc.Key words: rat; large intestine; carcinogenesis; PhIP; azoxymethane; no-observed effect level Carcinogenesis is widely accepted to be a multistep process caused by a series of genetic and/or subsequent epigenetic alterations that are indispensable to the different stages from initiation to promotion and progression of cancer development. 1,2 Humans are consistently exposed to very many naturally occurring or synthetic chemical carcinogens at quite low-dose levels in the environment, 3 although concomitantly they may consume mixtures of naturally occurring anticarcinogenic compounds in their daily diets. 4 One focus of attention has been food-derived heterocyclic amines (HCAs) generated in cooking processes that have proved to be carcinogenic in rodent species. 5,6 HCAs are highly mutagenic 6 and genotoxic carcinogens that are generally thought to have no threshold in exerting their carcinogenic potential, which was postulated to exhibit dose dependence in vivo. 3 However, in practice, low-dose administration has not necessarily led to cancer development in the rat liver. 7 Thereby, in our laboratory, the nonthreshold theory for hepatocarcinogenesis of one HCA, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), has been challenged, since in vivo dose-response curves do not show linearity at low-dose levels. 8,9 Moreover, thresholds for chemical carcinogenesis were concluded in a recent article. 10 In practice, the many factors active in vivo, from intake of carcinogens through to lesion development, mean that the processes are highly complicated, so that if the DNA-damaging pote...

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Analysis of K-ras, APC, and β-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis

Cited by 243 publications

References 34 publications

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

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

CpG island methylation in aberrant crypt foci and cancers from the same patients

Lack of large intestinal carcinogenicity of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine at low doses in rats initiated with azoxymethane

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