Human Molecular Genetics, 2002, Vol. 11, No. 13 1549-1560
© 2002 Oxford University Press
The ‘just-right’ signaling model: APC somatic mutations are selected based on a specific level of activation of the ß-catenin signaling cascade
1Centro de Investigação de Patobiologia Molecular–CIPM, Instituto Português de Oncologia Francisco Gentil, 1093 Lisbon, Portugal, 2Center for Human and Clinical Genetics, Leiden University Medical Center, PO Box 9503, 2300 RA Leiden, The Netherlands, 3Serviço de Gastrenterologia, Instituto Português de Oncologia Francisco Gentil, 1093 Lisbon, Portugal and 4Department of Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Received February 22, 2002; Accepted April 25, 2002
According to the classical interpretation of Knudson's ‘two-hit’ hypothesis for tumorigenesis, the two ‘hits’ are independent mutation events, the end result of which is loss of a tumor suppressing function. Recently, it has been shown that the APC (adenomatous polyposis coli) gene does not entirely follow this model. Both the position and type of the second hit in familial adenomatous polyposis (FAP) polyps depend on the localization of the germline mutation. This non-random distribution of somatic hits has been interpreted as the result of selection for more advantageous mutations during tumor formation. However, the APC gene encodes for a multifunctional protein, and the exact cellular function upon which this selection is based is yet unknown. In this study, we have analyzed somatic APC point mutations and loss of heterozygosity (LOH) in 133 colorectal adenomas from six FAP patients. We observed that when germline mutations result in truncated proteins without any of the seven ß-catenin downregulating 20-amino-acid repeats distributed in the central domain of APC, the majority of the corresponding somatic point mutations retain one or, less frequently, two of the same 20-amino-acid repeats. Conversely, when the germline mutation results in a truncated protein retaining one 20-amino-acid repeat, most second hits remove all 20-amino-acid repeats. The latter is frequently accomplished by allelic loss. Notably, and in contrast to previous observations, in a patient where the germline APC mutation retains two such repeats, the majority of the somatic hits are point mutations (and not LOH) located upstream and removing all of the 20-amino-acid repeats. These results indicate selection for APC genotypes that are likely to retain some activity in downregulating ß-catenin signaling. We propose that this selection process is aimed at a specific degree of ß-catenin signaling optimal for tumor formation, rather than at its constitutive activation by deletion of all of the ß-catenin downregulating motifs in APC.
* To whom correspondence should be addressed at: Center for Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands. Tel: +31 71 5276008; Fax: +31 71 5276075; E-mail: r.smits{at}lumc.nl
Present address: Rob van der Luijt, Department of Medical Genetics, University Medical Center Utrecht, Location WKZ, PO Box 85090, 3508 AB Utrecht, The Netherlands
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