Davies, R.; Al-Tassan, N.; Jones, S.; Chmiel, N.H.; Maynard, J.; Fleming, N.; Livingston, A.L.; Williams, G.T.; Hodges, A.K.; Dolwani, S.; David, S.S.; Cheadle, J.P.; Sampson, J.R.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA91
Academic Journal
Background: Multiple colorectal adenoma families have been identified that do not conform to classical FAP or HNPCC. We studied the somatic mutation profile of adenomas from affected siblings in one such family to establish the nature of their inherited defect. Method: Family 'N' consisted of seven siblings, 1 with colon cancer at the age of 46, which was associated with adenomas. Screening his siblings identified two with approximately 50 adenomatous colorectal polyps at the ages of 59 and 55, respectively. 11 tumours from these 3 affected siblings were screened for somatic APC gene mutations. Results: 18 somatic inactivating APC gene mutations were identified in these 11 tumours. Remarkably, 15 of these were G:C→T:A transversions. This type of mutation was significantly over-represented when compared to somatic mutations so far described in sporadic and FAP associated adenomas/adenocarcinomas. Similar mutations had previously been reported in DNA repair deficient yeast and bacteria. In E coli a series of enzymes function synergistically to protect cells from the deleterious effects of guanine oxidation. Analysis of the human homologue of mutY (MYH) showed that the affected siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These occur at sub-polymorphic frequency in the general population. Assays of glycosylase activity of the mutant proteins showed their activity was reduced significantly. This provided a link between inherited variants of MYH and the pattern of somatic APC mutation found in family N and implicated defective base excision repair in adenoma formation. Since the original report of family N, we have identified over 20 further families with multiple colorecta adenomas and biallelic germline MYH mutations, confirming the role of MYH in some families with colorectal polyposis. Conclusion: Germline mutations of the base excision repair gene MYH are a cause of multiple colorectal adenomas and...


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