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

The APC gene, originally identified as the gene for familiar adenomatous po lyposis (FAP), is now considered as the true "gatekeeper" of colonic epithe lial proliferation. Its main tumor suppressing activity seems to reside in the capacity to properly regulate intracellular beta-catenin signaling. Mos t somatic APC mutations are detected between codons 1286 and 1513, the muta tion cluster region (MCR). This clustering can be explained either by the p resence of mutation-prone sequences within the MCR, or by the selective adv antage provided by the resulting truncated polypeptides. Here, a Msh2-defic ient mouse model (Msh2(Delta 7N)) was generated and bred with Apc(1638N) an d Apc(Min) that allowed the comparison of the somatic mutation spectra alon g the Apc gene in the different allelic combinations. Mutations identified in Msh2(Delta 7N/Delta 7N) tumors are predominantly dinucleotide deletions at simple sequence repeats leading to truncated Ape polypeptides that parti ally retain the 20 a.a. beta-catenin downregulating motifs. In contrast, th e somatic mutations identified in the wild type Apc allele of Msh2(Delta 7N /Delta 7N)/ Apc(+/638N) and Msh(2 Delta 7N/Delta 7N)/Apc(+/Min) tumors are clustered more to the 5' end, thereby completely inactivating the beta-cate nin downregulating activity of APC. These results indicate that somatic Ape mutations are selected during intestinal tumorigenesis and that inactivati on of the beta-catenin downregulating function of APC is likely to represen t the main selective factor. (C) 2000 Wiley-Liss, Inc.