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Carcinogenesis Advance Access published online on March 2, 2006
Carcinogenesis, doi:10.1093/carcin/bgi373
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received January 13, 2006
Revised February 1, 2006
Accepted February 6, 2006

CANCER BIOLOGY

Epigenetic alterations in RASSF1A in human aberrant crypt foci

Emily J. Greenspan 1, Melissa Jablonski 1, T. V. Rajan 2, Joel Levine 3, Glenn Belinsky 1, and Daniel W. Rosenberg 4 *

1 Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT USA
2 Colon Cancer Prevention Program, Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, CT USA; Department of Pathology, University of Connecticut Health Center, Farmington, CT USA
3 Colon Cancer Prevention Program, Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, CT USA; Division of Gastroenterology, UCHC School of Medicine, University of Connecticut Health Center, Farmington, CT USA
4 Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT USA; Colon Cancer Prevention Program, Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, CT USA

* To whom correspondence should be addressed.
Daniel W. Rosenberg, E-mail: Rosenberg{at}nso1.uchc.edu


  Abstract

CpG island methylation (CIM) is an epigenetic mechanism for transcriptional silencing that occurs at various stages of colon tumorigenesis. CIM has been found in serrated adenomas and hyperplastic polyps. There is also evidence for hypermethylation in aberrant crypt foci (ACF) that are found in resected colons from cancer patients. Our study addresses promoter methylation of a tumor suppressor gene, RASSF1A, within the colonic epithelium of subjects undergoing screening colonoscopies in the absence of synchronous tumors. Patients included in this study were at elevated risk for colorectal cancer (CRC) based on family history, but without a previously occurring or synchronous colon carcinoma. ACF were identified using close-focus magnifying chromendoscopy and collected by biopsy in situ. We isolated ACF and adjacent normal colonic epithelium by laser capture microdissection (LCM) and studied methylation of the RASSF1A promoter region in ACF and in adjacent normal mucosa. Expression of RASSF1A was verified using quantitative real-time PCR (QRT-PCR). We found that 8.6% (3/35) of ACF had K-ras mutations and 24% (6/25) had RASSF1A hypermethylation. Our results demonstrate that RASSF1A hypermethylation and K-ras mutations are not mutually exclusive and are present in patients at elevated risk of CRC. Importantly, CIM of RASSF1A is an early epigenetic aberration, occurring in the absence of synchronous colon tumors and is not accompanied by field effects into the surrounding epithelium.


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