Published online 18 March 2005
Article |
Two modes of microsatellite instability in human cancer: differential connection of defective DNA mismatch repair to dinucleotide repeat instability
Institute for Clinical Research, National Kyushu Cancer Center Fukuoka 811-1395, Japan 1Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Fukuoka 812-8582, Japan 2Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences, Kyushu University Fukuoka 812-8582, Japan 3Division of Genetics, Tokyo Medical and Dental University Tokyo 113-8510, Japan 4Biomolecular Engineering Research Institute Suita, Osaka 565-0874, Japan 5Mammalian DNA Repair Laboratory, Cancer Research UK, London Research Institute, Clare Hall Laboratories South Mimms, Herts EN6 3LD, UK 6Biological Dose Section, Department of Dose Assessment, Research Center for Radiation Emergency Medicine, National Institute of Radiological Science Chiba 263-8555, Japan
*To whom correspondence should be addressed. Tel: +81 92 541 3231; Fax: +81 92 542 8534; Email: soda{at}nk-cc.go.jp
Received January 13, 2005. Revised February 24, 2005. Accepted February 24, 2005.
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Imai and H. Yamamoto Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics Carcinogenesis, April 1, 2008; 29(4): 673 - 680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. D. Kelkar, S. Tyekucheva, F. Chiaromonte, and K. D. Makova The genome-wide determinants of human and chimpanzee microsatellite evolution Genome Res., January 1, 2008; 18(1): 30 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. Young, A. M. Keuling, R. Lai, P. N. Nation, V. A. Tron, and S. E. Andrew The associated contributions of p53 and the DNA mismatch repair protein Msh6 to spontaneous tumorigenesis Carcinogenesis, October 1, 2007; 28(10): 2131 - 2138. [Abstract] [Full Text] [PDF]
|
|