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.
Sohn
Kyoung-Jin
KJ
Department of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
Choi
Monica
M
Song
Jacquelin
J
Chan
Sofeene
S
Medline
Alan
A
Gallinger
Steven
S
Kim
Young-In
YI
D000236:Adenoma / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins; D017491:Genes, APC; D016158:Genes, p53; D019656:Loss of Heterozygosity; D051379:Mice; D051718:MutS Homolog 2 Protein; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein