Carcinogenesis, Vol. 24, No. 2, 217-224,
February 2003
© 2003 Oxford University Press
CANCER BIOLOGY |
Msh2 deficiency enhances somatic Apc and p53 mutations in Apc+/–Msh2–/– mice
1 Department of Medicine,
2 Department of Nutritional Sciences,
3 Department of Laboratory Medicine and Pathobiology and
4 Department of Surgery, University of Toronto, Toronto, Ontario, M5S 1A8,
5 Samuel Lunenfeld Research Institute, Center for Cancer Genetics, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5 and
6 Division of Gastroenterology, Department of Medicine, St Michael’s Hospital, Toronto, Ontario, M5B 1W8, Canada
Inactivation of the adenomatous polyposis coli (Apc) gene by loss of the wild-type Apc allele (LOH) is a prerequisite for the development of intestinal adenomas in Msh2 proficient Min (Apc+/–Msh2+/+) mice. In contrast, adenomas from Msh2 deficient Min (Apc+/–Msh2–/–) mice are not usually associated with LOH. Given the role of Msh2 in post-replicative DNA repair, this study investigated whether Msh2 deficiency enhances somatic Apc and p53 mutations in Apc+/–Msh2–/– mice. Somatic Apc mutations (5/sample) were observed in the non-neoplastic intestinal mucosa from Apc+/–Msh2–/– mice but not from Min mice, suggesting that Msh2 deficiency is associated with a hypermutable state in the intestinal mucosa from Apc+/–Msh2–/– mice. Adenomas from Apc+/–Msh2–/– mice had a 2-fold higher rate of somatic Apc mutations (10/adenoma) than the non-neoplastic intestinal mucosa (5/sample), and did not demonstrate LOH. Truncating Apc mutations were observed in 82% of the adenomas from Apc+/–Msh2–/– mice and were not observed at all in the non-neoplastic intestinal mucosa. In contrast, in Min mice, all adenomas demonstrated LOH, had significantly less numbers of somatic Apc mutations (1.8 mutations/adenoma) compared with the adenomas from Apc+/–Msh2–/– mice, and harbored no truncating Apc mutations. These observations suggest that somatic Apc mutations, and not LOH, is a likely mechanism by which the Apc gene is inactivated in the development of adenomas in Apc+/–Msh2–/– mice in contrast to Min mice. Adenomas from Apc+/–Msh2–/– mice, but not from Min mice, also harbored somatic p53 mutations (mutation frequency of 45.5%), reflecting hypermutability associated with Msh2 deficiency. The nature and frequency of somatic Apc and p53 mutations in Apc+/–Msh2–/– mice suggest that many genomic sites, in addition to genes containing simple repeated sequences, are at risk of somatic mutations associated with Msh2 deficiency.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  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]
|
|
|
|
 |
|
 O. M. Sieber, K. M. Howarth, C. Thirlwell, A. Rowan, N. Mandir, R. A. Goodlad, A. Gilkar, B. Spencer-Dene, G. Stamp, V. Johnson, et al. Myh Deficiency Enhances Intestinal Tumorigenesis in Multiple Intestinal Neoplasia (ApcMin/+) Mice Cancer Res., December 15, 2004; 64(24): 8876 - 8881. [Abstract] [Full Text] [PDF]
|
|