Carcinogenesis Advance Access originally published online on November 28, 2007
Carcinogenesis 2008 29(2):434-439; doi:10.1093/carcin/bgm270
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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
Department of Pathology, GROW - School for Oncology and developmental biology, Maastricht University, Maastricht, 6200 MD, The Netherlands
1 Department of Pathology, VU University Medical Centre, Amsterdam, 1007 MB, The Netherlands
2 Department of Oncology, The Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins, Baltimore, MD 21231, USA
3 Department of Epidemiology, GROW-School for Oncology and developmental biology, Maastricht University, Maastricht, 6200 MD, The Netherlands
* To whom correspondence should be addressed. Tel: +31 43 3874622; Fax: +31 43 3876613; Email: 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 CRC-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 hMLH1, O6-MGMT, APC, p14ARF, p16INK4A, RASSF1A, GATA-4, GATA-5 and CHFR was analysed using methylation-specific polymerase chain reaction. These integrative analyses showed that in CIN+ CRCs, promoter methylation of GATA-4 and p16INK4A was inversely related to chromosomal loss at 15q11–q21 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 (MI), 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 hMLH1, APC and p16INK4A and a high MI (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 CRC, which are different from methylation patterns in MSI tumours.
Abbreviations: CAE, cancer-associated event; CGH, comparative genomic hybridization; CIMP, CpG island methylator phenotype; CIN, chromosomal instability; CRC, colorectal cancer; MI, methylation index; MMR, mismatch repair; MSI, microsatellite instability; PCR, polymerase chain reaction
Received August 13, 2007; revised October 12, 2007; accepted November 17, 2007.