Promoter methylation precedes chromosomal alterations in colorectal cancer development
Article type: Research Article
Authors: Derks, Sarah | Postma, Cindy | Moerkerk, Peter T.M. | van den Bosch, Sandra M. | Carvalho, Beatriz | Hermsen, Mario A.J.A. | Giaretti, Walter | Herman, James G. | Weijenberg, Matty P. | Bruïne, Adriaan P. de | Meijer, Gerrit A. | van Engeland, Manon;
Affiliations: Department of Pathology, Research Institute GROW, University Maastricht, The Netherlands | Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands | Present address: Dept. of Otolaryngology, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Hospital Central de Asturias, Oviedo, Spain | Department of Oncogenesis, Biophysics and Cytometry, National Institute for Cancer Research, Genoa, Italy | Department of Tumor Biology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA | Department of Epidemiology, Nutrition and Toxicology, Research Institute NUTRIM, University Maastricht, The Netherlands
Note: [] Corresponding author: Manon van Engeland, Dept. of Pathology, Research Institute GROW, University Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands. Tel.: +31 43 3874622; Fax: +31 43 3876613; E-mail: m.vanengeland@path.unimaas.nl
Abstract: Background: Colorectal cancers are characterized by genetic and epigenetic alterations. This study aimed to explore the timing of promoter methylation and relationship with mutations and chromosomal alterations in colorectal carcinogenesis. Methods: In a series of 47 nonprogressed adenomas, 41 progressed adenomas (malignant polyps), 38 colorectal carcinomas and 18 paired normal tissues, we evaluated promoter methylation status of hMLH1, O6MGMT, APC, p14ARF, p16INK4A, RASSF1A, GATA-4, GATA-5, and CHFR using methylation-specific PCR. Mutation status of TP53, APC and KRAS were studied by p53 immunohistochemistry and sequencing of the APC and KRAS mutation cluster regions. Chromosomal alterations were evaluated by comparative genomic hybridization. Results: Our data demonstrate that nonprogressed adenomas, progressed adenomas and carcinomas show similar frequencies of promoter methylation for the majority of the genes. Normal tissues showed significantly lower frequencies of promoter methylation of APC, p16INK4A, GATA-4, and GATA-5 (P-values: 0.02, 0.02, 1.1×10−5 and 0.008 respectively). P53 immunopositivity and chromosomal abnormalities occur predominantly in carcinomas (P values: 1.1×10−5 and 4.1×10−10). Conclusions: Since promoter methylation was already present in nonprogressed adenomas without chromosomal alterations, we conclude that promoter methylation can be regarded as an early event preceding TP53 mutation and chromosomal abnormalities in colorectal cancer development.
Keywords: Colorectal cancer, promoter methylation, genetic alterations, chromosomal instability
Journal: Analytical Cellular Pathology, vol. 28, no. 5-6, pp. 247-257, 2006
