Somatic Apc mutations are selected upon their capacity to inactivate the β-catenin downregulating activity

Ron Smits, Nandy Hofland, Winfried Edelmann, Marjan Geugien, Shantie Jagmohan-Changur, Cristina Albuquerque, Cor Breukel, Raju Kucherlapati, Menno F. Kielman, Riccardo Fodde

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Abstract

The APC gene, originally identified as the gene for familial adenomatous polyposis (FAP), is now considered as the true 'gatekeeper' of colonic epithelial proliferation. Its main tumor suppressing activity seems to reside in the capacity to properly regulate intracellular β-catenin signaling. Most somatic APC mutations are detected between codons 1286 and 1513, the mutation cluster region (MCR). This clustering can be explained either by the presence of mutation-prone sequences within the MCR, or by the selective advantage provided by the resulting truncated polypeptides. Here, a Msh2-deficient mouse model (Msh2(Δ7N)) was generated and bred with Apc(1638N) and Apc(Min) that allowed the comparison of the somatic mutation spectra along the Apc gene in the different allelic combinations. Mutations identified in Msh2(Δ7N/Δ7N) tumors are predominantly dinucleotide deletions at simple sequence repeats leading to truncated Apc polypeptides that partially retain the 20 a.a. β-catenin downregulating motifs. In contrast, the somatic mutations identified in the wild type Apc allele of Msh2(Δ7N/Δ7N/Apc(+/1638N) and Msh2(Δ7N/Δ7N)/Apc(+Min) tumors are clustered more to the 5' end, thereby completely inactivating the β-catenin downregulating activity of APC. These results indicate that somatic Apc mutations are selected during intestinal tumorigenesis and that inactivation of the β-catenin downregulating function of APC is likely to represent the main selective factor. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)229-239
Number of pages11
JournalGenes Chromosomes and Cancer
Volume29
Issue number3
DOIs
StatePublished - Oct 14 2000

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ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

Smits, R., Hofland, N., Edelmann, W., Geugien, M., Jagmohan-Changur, S., Albuquerque, C., Breukel, C., Kucherlapati, R., Kielman, M. F., & Fodde, R. (2000). Somatic Apc mutations are selected upon their capacity to inactivate the β-catenin downregulating activity. Genes Chromosomes and Cancer, 29(3), 229-239. https://doi.org/10.1002/1098-2264(2000)9999:9999<::AID-GCC1033>3.0.CO;2-R