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Carcinogenesis Advance Access published online on November 28, 2007
Carcinogenesis, doi:10.1093/carcin/bgm270
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Integrated analysis of chromosomal, microsatellite and epigenetic instability in colorectal cancer identifies specific associations between promoter methylation of pivotal tumour suppressor and DNA repair genes and specific chromosomal alterations

Sarah Derks1, Cindy Postma2, Beatriz Carvalho2, Sandra M van den Bosch1, Peter TM Moerkerk1, James G Herman3, Matty P Weijenberg4, Adriaan P de Bruïne1, Gerrit A Meijer2 and Manon van Engeland1,*

1 Department of Pathology, Research Institute GROW, School for Oncology and Developmental Biology, University Maastricht, The Netherlands
2 Department of Pathology, VU University Medical Centre, Amsterdam The Netherlands
3 Dept. of Oncology, The Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins, Baltimore, Maryland, USA
4 Dept of Epidemiology, Research Institute GROW, School for Oncology and Developmental Biology, University Maastricht, The Netherlands

* Author for correspondence: 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{at}path.unimaas.nl

Colorectal cancer (CRC) is a complex and heterogeneous disease in which genomic instability and DNA promoter methylation play important roles. The aim of this study was to investigate the relationship between chromosomal instability (CIN), microsatellite instability (MSI) and promoter methylation of colorectal cancer associated genes. Therefore 71 CRCs were analysed for CIN and MSI by comparative genomic hybridization and the mononucleotide marker BAT-26 respectively. Promoter methylation of the tumour suppressor and DNA repair genes hMHL1, O6-MGMT, APC, p14ARF, p16INK4A, RASSF1A, GATA-4, GATA-5 and CHFR was analysed using methylation-specific PCR (MSP). These integrative analyses showed that in CIN+ CRCs, promoter methylation of GATA-4 and p16INKA4 was inversely related to chromosomal loss at 15q11-21 and gain at 20q13 respectively (P values: 3.8 x 10-2 and 4.5 x 10-2 respectively). Interestingly, promoter methylation of RASSF1A, GATA-4, GATA-5 and CHFR as well as a high methylation index was positively related to chromosomal gain at 8q23-qter (P values: 1.5 x 10-2, 3.8 x 10-2, 3.9 x 10-2 , 4,9 x 10-2 and 8.2 x 10-3 respectively). MSI was associated with BRAF mutation, promoter methylation of hMHL1, APC and p16INK4A and a high methylation index (total number of methylated genes) (P values: 2.4 x 10-2, 2.5 x 10-3, 1.8 x 10-2, 4.6 x 10-2 and 1.0 x 10-2 respectively). Therefore we conclude that promoter methylation of pivotal tumour suppressor and DNA repair genes is associated with specific patterns of chromosomal changes in colorectal cancer, which is different from methylation patterns in MSI tumours.

Key Words: colorectal cancer • chromosomal instability • microsatellite instability • DNA methylation

Received August 13, 2007; revised October 12, 2007; accepted November 17, 2007.


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