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Carcinogenesis Advance Access published online on September 16, 2004
Carcinogenesis, doi:10.1093/carcin/bgh280
© 2004 by Oxford University Press
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Received April 26, 2004
Revised August 27, 2004
Accepted September 5, 2004

CANCER BIOLOGY

Molecular analysis of APC promoter methylation and protein expression in colorectal cancer metastasis

Jie Chen 1, Christoph Röcken 2, Cathy Lofton-Day 3, Hans-Ulrich Schulz 4, Oliver Müller 5, Nadine Kutzner 5, Peter Malfertheiner 1, and Matthias P. A. Ebert 1*

1 Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
2 Institute of Pathology, Otto-von-Guericke University, Magdeburg, Germany
3 Epigenomics Inc., Seattle, WA, USA
4 Department of General Surgery, Otto-von-Guericke University, Magdeburg, Germany
5 Max-Planck-Institute of Molecular Physiology, Dortmund, Germany

* To whom correspondence should be addressed. E-mail: Matthias.Ebert{at}medizin.uni-magdeburg.de.


  Abstract

APC (adenomatous polyposis coli) promoter methylation has been linked to the early development of colorectal cancers. However, the role of APC methylation and its effect on protein expression in colon cancer metastasis is largely unknown. In this study, we studied APC promoter methylation by Methylight analysis and analysed the APC protein levels by immunohistochemistry and Western blot analysis in 24 liver metastasis and 39 primary colorectal cancers. Promoter methylation of the APC gene was found to be a frequent event in liver metastasis (10/24) and significantly more frequent compared to primary colorectal cancer (7/39, p=0.047). APC methylation was not found in 14 matched normal colon tissues. APC protein was detected in the cytoplasm of primary and metastatic cancer cells and non-tumorous colon epithelium. By Western blot analysis, APC protein levels were found to be decreased in primary tumor tissues compared to the normal colon mucosa. In contrast, APC protein levels were not decreased in the cancer cells that had metastasised to the liver. APC protein levels were independent of the presence of APC promoter methylation or gene mutations. In summary, APC promoter methylation is a frequent epigenetic alteration in colorectal cancer metastasis. However, we observed no significant association between APC promoter methylation or gene mutation and APC protein expression in colorectal metastasis. Therefore, metastatic cancer cells seem to harbour a heterogenous genetic and epigenetic background, in which cancer cells may exhibit APC promoter methylation that is independent of APC expression.

Keywords: colon cancer; metastasis; APC; methylation; mutation; expression.
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