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(American Journal of Pathology. 2003;162:1545-1548.)
© 2003 American Society for Investigative Pathology

Germline Mutations but Not Somatic Changes at the MYH Locus Contribute to the Pathogenesis of Unselected Colorectal Cancers

Sarah E. R. Halford^*, Andrew J. Rowan^*, Lara Lipton^*, Oliver M. Sieber^*, Kevin Pack, Huw J. W. Thomas, Shirley V. Hodgson, Walter F. Bodmer and Ian P. M. Tomlinson^*

From the Molecular and Population Genetics Laboratory,^* London Institute, Cancer Research United Kingdom, London; the Colorectal Cancer Unit, Cancer Research United Kingdom, St. Mark’s Hospital, Harrow; the Department of Clinical Genetics, Guy’s Hospital, London; and the Cancer and Immunogenetics Laboratory, Cancer Research United Kingdom, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom

MYH-associated polyposis is a recently described, autosomal recessive condition comprising multiple colorectal adenomas and cancer. This disease is caused by germline mutations in the base excision repair (BER) gene MYH. Genes involved in the BER pathway are thus good candidates for involvement in the pathogenesis of sporadic tumors of the large bowel. We have screened a set of 75 sporadic colorectal cancers for mutations in MYH, MTH1, and OGG1. Allelic loss at MYH was also assessed. Selected samples were screened for mutations and allele loss at APC and mutations in p53, K-ras, and ß-catenin. A panel of 35 colorectal cancer cell lines was screened for MYH mRNA and protein expression. One of 75 cancers had bi-allelic germline mutations in MYH and on retrospective analysis of medical records this patient was found to have synchronous multiple small adenomas in addition to carcinoma. No somatic MYH mutations were found and mRNA and protein were expressed in all of our cell lines. There were no clearly pathogenic mutations in MTH1 or OGG1 in any tumor. Bi-allelic germline MYH mutations cause 1 to 3% of unselected colorectal cancers, but appear always to be associated with multiple adenomas. Somatic inactivation of the DNA glycosylases involved in the BER pathway however does not appear to be involved in colorectal tumorigenesis.

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