Tumor-associated Apc mutations in Mlh1(-/-) Apc(1638N) mice reveal a mutational signature of Mlh1 deficiency

Mari Kuraguchi, Winfried Edelmann, Kan Yang, Martin Lipkin, Raju Kucherlapati, Anthony MC Brown

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Apc(1638N) mice, which are heterozygous for a germline mutation in Apc, typically develop three to five spontaneous intestinal tumors per animal. In most cases this is associated with allelic loss of wildtype Apc. We have previously reported that the multiplicity of intestinal tumors is increased dramatically by crossing Apc(1638N) with an Mlh1-deficient mouse strain that represents an animal model of hereditary non-polyposis colorectal cancer (HNPCC). The increased tumor multiplicity in these mice was associated with somatic mutations in the Apc tumor suppressor gene. Here, we have examined the nature and distribution of 91 Apc mutations implicated in the development of intestinal tumors in Mlh1(-/-) Apc(1638N) animals. Protein truncation mutations were detected in a majority of tumor samples, indicating that the prevailing mechanism of Apc mutation in tumors is altered from allelic loss to intragenic mutation as a result of Mlh1 deficiency. The observed mutations were a mixture of base substitutions (27%) and frameshifts (73%). Most frameshifts were detected within dinucleotide repeats and there were prominent mutational hotspots within sequences of this sort at codons 927-929, 1209-1211 and 1461-1464. The observed Apc mutations caused protein truncation upstream of the third 20 amino acid β-catenin binding domain and the first Axin-binding SAMP repeat, yielding Ape proteins that are predicted to be deficient in destabilizing β-catenin. Our results reveal a characteristic mutational signature in Apc that is attributable to Mlh1 deficiency. This demonstrates a direct effect of Mlh1 deficiency in the mutation of Apc in these tumors, and provides data that clarify the role of Mlh1 in mammalian DNA mismatch repair.

Original languageEnglish (US)
Pages (from-to)5755-5763
Number of pages9
JournalOncogene
Volume19
Issue number50
DOIs
StatePublished - Nov 23 2000

Keywords

  • Apc
  • Colorectal cancer
  • Mlh1
  • Mouse models
  • Mutation analysis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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