Journal Article

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 Derks, Cindy Postma, Beatriz Carvalho, Sandra M. van den Bosch, Peter T.M. Moerkerk, James G. Herman, Matty P. Weijenberg, Adriaan P. de Bruïne, Gerrit A. Meijer and Manon van Engeland

in Carcinogenesis

Volume 29, issue 2, pages 434-439
Published in print February 2008 | ISSN: 0143-3334
Published online November 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm270
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

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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 × 10−2 and 4.5 × 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 × 10−2, 3.8 × 10−2, 3.9 × 10−2, 4.9 × 10−2 and 8.2 × 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 × 10−2, 2.5 × 10−3, 1.8 × 10−2, 4.6 × 10−2 and 1.0 × 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.

Journal Article.  4484 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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