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1 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research United Kingdom, London, United Kingdom;
2 Cancer Research United Kingdom Colorectal Cancer Unit, St. Mark’s Hospital, Harrow United Kingdom;
3 Department of Histopathology, University College London Hospitals, London, United Kingdom;
4 Danish Polyposis Registry, Hvidovre Hospital, Copenhagen, Denmark;
5 Department of Clinical Genetics, St. George’s Hospital Medical School, London, United Kingdom;
6 Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland
Colorectal carcinomas develop according to particular genetic pathways, including the chromosomal instability (CIN+), microsatellite instability (MSI+) and MSI- CIN- routes. We have determined the genetic pathway in patients with MYH-associated polyposis (MAP), a syndrome of colorectal adenomas and cancer that results from defective base excision repair (BER). As in previous studies, MAP tumors showed a high frequency of G>T mutations in APC, in accordance with defective BER. We found that K-ras mutations were common in MAP tumors, all of the changes comprising conversion of the first guanine residue of codon 12 to thymidine (G12C, GGT>TGT). We found no BRAF mutations at the codon 599 hotspot or elsewhere in exon 14. Almost all of the MAP cancers were near-diploid (CIN-), and none was MSI+. A few p53 mutations were found, but these were not predominantly G>T changes. p53 overexpression was, however, frequent. No SMAD4 or TGFBIIR mutations were found. MAP tumors appear to follow a distinct genetic pathway, with some features of both the CIN and MSI pathways. BER deficiency is rarely accompanied by CIN or MSI. The spectrum of somatic mutations in MAP tumors reflects both selection and hypermutation to which certain guanine residues are particularly prone.
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