Journal Article

Msh2 deficiency enhances somatic <i>Apc</i> and <i>p53</i> mutations in <i>Apc+/–Msh2–/–</i> mice

Kyoung-Jin Sohn, Monica Choi, Jacquelin Song, Sofeene Chan, Alan Medline, Steven Gallinger and Young-In Kim

in Carcinogenesis

Volume 24, issue 2, pages 217-224
Published in print February 2003 | ISSN: 0143-3334
Published online February 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/24.2.217
Msh2 deficiency enhances somatic Apc and p53 mutations in Apc+/–Msh2–/– mice

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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.

Keywords: Apc, adenomatous polyposis coli; CRC, colorectal cancer; LOH, loss of heterozygosity; MCR, mutation cluster region; MMR, mismatch repair; RER, replication error

Journal Article.  6786 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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