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

• Published in: Carcinogenesis (New York) Vol. 29; no. 2; pp. 434 - 439
• Main Authors: Derks, Sarah, Postma, Cindy, Carvalho, Beatriz, van den Bosch, Sandra M., Moerkerk, Peter T.M., Herman, James G., Weijenberg, Matty P., de Bruïne, Adriaan P., Meijer, Gerrit A., van Engeland, Manon
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-02-2008; Oxford Publishing Limited (England)
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Chromosomes - ultrastructure; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; DNA Methylation; DNA Repair; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Genetic Predisposition to Disease; Humans; Male; Medical sciences; Middle Aged; Promoter Regions, Genetic; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Rectal disease; Transcription promoter; Toxicity; Colorectal cancer; Alteration; Chromosome; Malignant tumor; DNA repair; Repair gene; Colonic disease; Association; DNA; Epigenetics; Digestive diseases; Intestinal disease; Genetics; Instability; Methylation; Cancer; Tumor suppressor gene
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgm270

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.