Human Molecular Genetics Advance Access originally published online on November 29, 2006
Human Molecular Genetics 2007 16(1):78-82; doi:10.1093/hmg/ddl442
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APC mutations in FAP-associated desmoid tumours are non-random but not ‘just right’
1 Polyposis Registry and 2 Colorectal Cancer Genetics, Cancer Research UK, St Mark's Hospital, Harrow, Middlesex HA1 3UJ, UK, 3 Institute of Cell and Molecular Science and Barts and the London Queen Mary's School of Medicine and Dentistry, London E1 2AT, UK and 4 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK
* To whom correspondence should be addressed at. Tel: +44 02078822590; Fax: +44 02078822200; Email: a.r.silver{at}qmul.ac.uk
Received September 15, 2006; Revised November 7, 2006; Accepted November 16, 2006
Analysis of APC mutations in colonic and duodenal tumours from familial adenomatous polyposis (FAP) patients has shown that the site of the first hit, the germline mutation, can predict the type and position of the somatic mutation or ‘second hit’. The two APC mutations are selected on the basis of a ‘just right’ level of beta-catenin signalling in intestinal tumours achieved through retention of some of the seven 20-amino-acid beta-catenin degradation repeats. Desmoids are a life threatening extra-colonic manifestation in FAP patients. These aggressive tumours of mesenchymal origin are, at present, poorly characterized in terms of mutational APC spectra. We have investigated somatic mutations in the largest cohort of FAP-associated desmoids to date, and combined our results with previously published data. Somatic mutations were found to occur non-randomly and the position of the germline mutation shown to be a major determinant of the somatic mutation, a characteristic shared with intestinal tumours from FAP patients. In contrast to colonic polyps, loss of heterozygosity in desmoids involved deletion rather than mitotic recombination. While tumours from the colorectum and upper gastrointestinal tract usually retain one to two and three to four beta-catenin degradation repeats, respectively, most desmoids preferentially retain two repeats (P < 0.001, 
2 test). In addition, most desmoids with two APC hits (87%, 26/30) had one mutated allele with no 20-amino acid repeats (P < 0.001). This feature, unique among FAP tumours, indicates that a mutation deleting all repeats from one allele may be an important component in maintaining appropriate levels of beta-catenin signalling levels in desmoid tumour cells.