Two modes of microsatellite instability in human cancer: Differential connection of defective DNA mismatch repair to dinucleotide repeat instability

Shinya Oda, Yoshihiko Maehara, Yoichi Ikeda, Eiji Oki, Akinori Egashira, Yoshikazu Okamura, Ikuo Takahashi, Yoshihiro Kakeji, Yasushi Sumiyoshi, Kaname Miyashita, Yu Yamada, Yan Zhao, Hiroyoshi Hattori, Ken Ichi Taguchi, Tatsuro Ikeuchi, Teruhisa Tsuzuki, Mutsuo Sekiguchi, Peter Karran, Mitsuaki A. Yoshida

研究成果: ジャーナルへの寄稿記事

51 引用 (Scopus)

抜粋

Microsatellite instability (MSI) is associated with defective DNA mismatch repair in various human malignancies. Using a unique fluorescent technique, we have observed two distinct modes of dinucleotide microsatellite alterations in human colorectal cancer. Type A alterations are defined as length changes of ≤6 bp. Type B changes are more drastic and involve modifications of ≥8 bp. We show here that defective mismatch repair is necessary and sufficient for Type A changes. These changes were observed in cell lines and in tumours from mismatch repair gene-knockout mice. No Type B instability was seen in these cells or tumours. In a panel of human colorectal tumours, both Type A MSI and Type B instability were observed. Both types of MSI were associated with hMSH2 or hMLH1 mismatch repair gene alterations. Intriguingly, p53 mutations, which are generally regarded as uncommon in human tumours of the MSI+ phenotype, were frequently associated with Type A instability, whereas none was found in tumours with Type B instability, reflecting the prevailing viewpoint. Inspection of published data reveals that the microsatellite instability that has been observed in various malignancies, including those associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is predominantly Type B. Our findings indicate that Type B instability is not a simple reflection of a repair defect. We suggest that there are at least two qualitatively distinct modes of dinucleotide MSI in human colorectal cancer, and that different molecular mechanisms may underlie these modes of MSI. The relationship between MSI and defective mismatch repair may be more complex than hitherto suspected.

元の言語英語
ページ(範囲)1628-1636
ページ数9
ジャーナルNucleic acids research
33
発行部数5
DOI
出版物ステータス出版済み - 10 17 2005

All Science Journal Classification (ASJC) codes

  • Genetics

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    Oda, S., Maehara, Y., Ikeda, Y., Oki, E., Egashira, A., Okamura, Y., Takahashi, I., Kakeji, Y., Sumiyoshi, Y., Miyashita, K., Yamada, Y., Zhao, Y., Hattori, H., Taguchi, K. I., Ikeuchi, T., Tsuzuki, T., Sekiguchi, M., Karran, P., & Yoshida, M. A. (2005). Two modes of microsatellite instability in human cancer: Differential connection of defective DNA mismatch repair to dinucleotide repeat instability. Nucleic acids research, 33(5), 1628-1636. https://doi.org/10.1093/nar/gki303