Journal Article

Screening for genomic fragments that are methylated specifically in colorectal carcinoma with a methylated <i>MLH1</i> promoter

Koji Koinuma, Ruri Kaneda, Minoru Toyota, Yoshihiro Yamashita, Shuji Takada, Young Lim Choi, Tomoaki Wada, Masaki Okada, Fumio Konishi, Hideo Nagai and Hiroyuki Mano

in Carcinogenesis

Volume 26, issue 12, pages 2078-2085
Published in print December 2005 | ISSN: 0143-3334
Published online July 2005 | e-ISSN: 1460-2180 | DOI:
Screening for genomic fragments that are methylated specifically in colorectal carcinoma with a methylated MLH1 promoter

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A subset of colorectal carcinomas (CRCs) is associated with microsatellite instability (MSI) of the genome. Although extensive methylation of CpG islands within the promoter regions of DNA mismatch repair genes such as MLH1 is thought to play a central role in tumorigenesis for MSI-positive sporadic CRCs, it has been obscure whether such aberrant epigenetic regulation occurs more widely and affects other cancer-related genes in vivo. Here, by using methylated CpG island amplification coupled with representational difference analysis (MCA–RDA), we screened genomic fragments that are selectively methylated in CRCs positive for MLH1 methylation, resulting in the identification of hundreds of CpG islands containing genomic fragments. Methylation status of such CpG islands was verified for 28 genomic clones in 8 CRC specimens positive for MLH1 methylation and the corresponding paired normal colon tissue as well as in 8 CRC specimens negative for methylation. Many of the CpG islands were preferentially methylated in the MLH1 methylation-positive CRC specimens, although methylation of some of them was more widespread. These data provide insights into the complex regulation of the methylation status of CpG islands in CRCs positive for MSI and MLH1 methylation.

Keywords: CRC, colorectal carcinoma; COBRA, combined bisulfite restriction analysis; CIMP, CpG island methylator phenotype; EGF, epidermal growth factor; GDF, growth-differentiation factor; MSI, microsatellite instability; MMR, mismatch repair; PCR, polymerase chain reaction; TGF-β, transforming growth factor-β

Journal Article.  4920 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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