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

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.