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Msh2 deficiency enhances somatic Apc and p53 mutations in Apc+/-Msh2-/- mice
Kyoung-Jin Sohn1, Monica Choi, Jacquelin Song
1Department of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
Abstract:
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.
Insights
Mice lacking Msh2 DNA repair show increased somatic mutations in Apc and p53 genes, leading to intestinal adenomas. This contrasts with Msh2-proficient mice where loss of heterozygosity is the primary driver.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Adenomatous polyposis coli (Apc) gene inactivation is crucial for intestinal adenoma development.
- Loss of heterozygosity (LOH) is the established mechanism for Apc inactivation in Msh2-proficient Min mice.
- Msh2 is vital for post-replicative DNA repair.
Purpose of the Study:
- To investigate if Msh2 deficiency enhances somatic Apc and p53 mutations in Apc+/-Msh2-/- mice.
- To compare mutation mechanisms in Msh2-proficient and Msh2-deficient intestinal adenomas.
- To assess the impact of Msh2 deficiency on intestinal mucosa hypermutability.
Main Methods:
- Comparative analysis of Apc and p53 mutations in intestinal adenomas and non-neoplastic mucosa.
- Genotyping of Apc and Msh2 alleles in mouse models (Apc+/-Msh2+/+ vs. Apc+/-Msh2-/-).
- Assessment of LOH and somatic mutation frequency in Apc and p53 genes.
Main Results:
- Msh2 deficiency leads to a hypermutable state in intestinal mucosa, with increased somatic Apc mutations.
- Adenomas in Apc+/-Msh2-/- mice exhibit a 2-fold higher rate of somatic Apc mutations and lack LOH.
- Truncating Apc mutations are prevalent in Msh2-deficient adenomas, unlike in Min mice.
- Somatic p53 mutations are frequent in Msh2-deficient adenomas, indicating widespread genomic instability.
Conclusions:
- Somatic Apc mutations, not LOH, are the primary mechanism for Apc inactivation in Msh2-deficient intestinal adenomas.
- Msh2 deficiency drives intestinal tumorigenesis through enhanced somatic mutations in critical cancer genes like Apc and p53.
- Msh2 deficiency poses a risk for somatic mutations across various genomic sites, beyond simple repeats.