Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2002 May;160(5):1823-30.
doi: 10.1016/S0002-9440(10)61128-5.

CpG island methylation in aberrant crypt foci of the colorectum

Annie On-On Chan  1 , Russell R Broaddus, Patrick S Houlihan, Jean-Pierre J Issa, Stanley R Hamilton, Asif Rashid
Affiliations

CpG island methylation in aberrant crypt foci of the colorectum

Annie On-On Chan et al. Am J Pathol. 2002 May.

Abstract

Aberrant crypt foci (ACF) are postulated to be the earliest precursor lesion in colorectal carcinogenesis, and CpG island methylation has been described as an important molecular pathway. We therefore studied methylation in ACF from patients with familial adenomatous polyposis (FAP) or sporadic colorectal cancer. We assessed methylation status of the p16 tumor suppressor gene, MINT1 (methylated in tumor 1), MINT2, MINT31, O(6)-methylguanine-DNA methyltransferase gene, and hMLH1 mismatch repair gene. We compared methylation to ACF histopathology, K-ras proto-oncogene mutation, loss of heterozygosity at chromosome 1p, and microsatellite instability. Methylation was present in 34% (21 of 61) of ACF, including both FAP and sporadic types, but was more frequent in sporadic ACF [53% (18 of 34) versus 11% (3 of 27), P = 0.002], especially dysplastic sporadic ACF [75% (3 of 4) versus 8% (2 of 24), P = 0.004]. MINT31 was more frequently methylated in heteroplastic ACF than dysplastic ACF [35% (11 of 31) versus 7% (2 of 30), P = 0.01]. Strong associations of ACF methylation with K-ras mutation (P = 0.007) and with loss of chromosome 1p (P = 0.04) were observed, but methylation was the only molecular abnormality identified in 16% (10 of 61) of ACF. Our findings suggest that methylation in ACF is an early event in the pathogenesis of a subset of colorectal carcinomas, and that ACF from FAP patients and patients with sporadic colorectal cancer have distinct epigenetic changes that reflect differences in molecular pathogenesis.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Histopathology of ACF. Heteroplastic ACF (top two panels), mixed heteroplastic and dysplastic ACF (third panel), and dysplastic ACF (bottom panel).
Figure 2.
Figure 2.
A: Methylation analysis of CpG islands in ACF. Examples of methylation of p16, MINT1, MINT31, and MGMT are shown. Methylation-specific PCR using primers for methylated (M) and unmethylated (U) alleles of bisulfite-treated DNA was performed. Loci examined and ACF numbers are indicated above each gel. MW represents lane with molecular weight marker. B: Nucleotide sequencing of the K-ras gene in ACF. A G-to-A mutation of codon 12 is indicated by the arrowhead. C: Allelic loss of chromosome 1p in ACF. The lane from normal DNA (N) has two alleles at marker D1S199 and the lane from the tumor DNA (T) shows loss of one of the alleles.
Figure 2.
Figure 2.
A: Methylation analysis of CpG islands in ACF. Examples of methylation of p16, MINT1, MINT31, and MGMT are shown. Methylation-specific PCR using primers for methylated (M) and unmethylated (U) alleles of bisulfite-treated DNA was performed. Loci examined and ACF numbers are indicated above each gel. MW represents lane with molecular weight marker. B: Nucleotide sequencing of the K-ras gene in ACF. A G-to-A mutation of codon 12 is indicated by the arrowhead. C: Allelic loss of chromosome 1p in ACF. The lane from normal DNA (N) has two alleles at marker D1S199 and the lane from the tumor DNA (T) shows loss of one of the alleles.
Figure 3.
Figure 3.
CIM, loss of chromosome 1p, K-ras mutation, and histopathology of ACF from FAP patients and patients with sporadic CRC.
See this image and copyright information in PMC

References

    1. Nucci MR, Robinson CR, Longo P, Campbell P, Hamilton SR: Phenotypic and genotypic characteristics of aberrant crypt foci in human colorectal mucosa. Hum Pathol 1997, 28:1396-1407 - PubMed
    1. Pretlow TP, Brasitus TA, Fulton NC, Cheyer C, Kaplan EL: K-ras mutations in putative preneoplastic lesions in human colon. J Natl Cancer Inst 1993, 85:2004-2007 - PubMed
    1. Heinen CD, Shivapurkar N, Tang Z, Groden J, Alabaster O: Microsatellite instability in aberrant crypt foci from human colons. Cancer Res 1996, 56:5339-5341 - PubMed
    1. Yamashita N, Minamoto T, Ochiai A, Onda M, Esumi H: Frequent and characteristic K-ras activation and absence of p53 protein accumulation in aberrant crypt foci of the colon. Gastroenterology 1995, 108:434-440 - PubMed
    1. Otori K, Konishi M, Sugiyama K, Hasebe T, Shimoda T, Kikuchi-Yanoshita R, Mukai K, Fukushima S, Miyaki M, Esumi H: Infrequent somatic mutation of the adenomatous polyposis coli gene in aberrant crypt foci of human colon tissue. Cancer 1998, 83:896-900 - PubMed

Publication types

MeSH terms