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Somatic Apc mutations are selected upon their capacity to inactivate the β‐catenin downregulating activity
Author(s) -
Smits Ron,
Hofland Nandy,
Edelmann Winfried,
Geugien Marjan,
JagmohanChangur Shantie,
Albuquerque Cristina,
Breukel Cor,
Kucherlapati Raju,
Kielman Menno F.,
Fodde Riccardo
Publication year - 2000
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/1098-2264(2000)9999:9999<::aid-gcc1033>3.0.co;2-r
Subject(s) - msh2 , adenomatous polyposis coli , familial adenomatous polyposis , mutation , biology , somatic cell , gene , genetics , germline mutation , carcinogenesis , microbiology and biotechnology , allele , cancer research , cancer , dna mismatch repair , colorectal cancer , dna repair
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. © 2000 Wiley‐Liss, Inc.