1. ¹Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK
2. ²Cancer Research UK Colorectal Cancer Unit, St Mark's Hospital, Watford Road, Harrow HA1 3UJ, UK
3. ³Department of Histopathology, Rockefeller Building, University College London, London WC1E 6BT, UK
4. ⁴Institute of Cancer, Bart's and the London Medical School, Queen Mary College, London, UK

Correspondence: Professor IPM Tomlinson, E-mail: ian.tomlinson@cancer.org.uk

Received 20 February 2007; Revised 13 April 2007; Accepted 18 April 2007; Published online 15 May 2007.

Abstract

Patients with multiple (5–100) colorectal adenomas (MCRAs) often have no germline mutation in known predisposition genes, but probably have a genetic origin. We collected a set of 25 MCRA patients with no detectable germline mutation in APC, MYH/MUTYH or the mismatch repair genes. Extracolonic tumours were absent in these cases. No vertical transmission of the MCRA phenotype was found. Based on the precedent of MYH-associated polyposis (MAP), we searched for a mutational signature in 241 adenomatous polyps from our MCRA cases. Somatic mutation frequencies and spectra at APC, K-ras and BRAF were, however, similar to those in sporadic colorectal adenomas. Our data suggest that the genetic pathway of tumorigenesis in the MCRA patients' tumours is very similar to the classical pathway in sporadic adenomas. In sharp contrast to MAP tumours, we did not find evidence of a specific mutational signature in any individual patient or in the overall set of MCRA cases. These results suggest that hypermutation of APC does not cause our patients' disease and strongly suggests that MAP is not a paradigm for the remaining MCRA patients. Our MCRA patients' colons showed no evidence of microadenomas, unlike in MAP and familial adenomatous polyposis (FAP). However, nuclear -catenin expression was significantly greater in MCRA patients' tumours than in sporadic adenomas. We suggest that, at least in some cases, the MCRA phenotype results from germline variation that acts subsequent to tumour initiation, perhaps by causing more rapid or more likely progression from microadenoma to macroadenoma.