Sieber, O.M.; Lipon, L.; Jones, S.; Heinimann, K.; Barclay, E.; Hodgson, S.V.; Cheadle, J.P.; Orntoft, T.F.; Aaltonen, L.A.; Sampson, J.R.; Tomlinson, I.P.M.; Thomas, H.J.W.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA29
Academic Journal
Background: Compound heterozygosity for missense variants of the base excision repair (BER) gene MYH has been linked to inheritance of multiple colorectal adenomas or carcinoma in a single UK family. Colorectal adenomas From affected individuals displayed an excess of somatic G:C→T:A transversions in the adenomatous polyposis coli (APC) gene, consistent with a BER defect. Methods: 157 unrelated UK patients with multiple (3 to 115) colorectal adenomas were screened for germ line mutations in MYH and subsets were screened for the related BER genes, MTH1 and OGG1. Adenomas from patients harbouring pathogenic MYH germ line mutations were tested for somatic APC mutations and loss of heterozygosity at MYH. Clinicopathological and molecular data were compared between patients with and without MYH mutations. Results: Fourteen (9%) patients harboured germ line MYH variants, with 8 (5%) having biallelic, pathogenic mutations. Both nonsense and protein truncating MYH mutations were found. Missense variants Y165C and G382D were the most frequent alterations observed. Patients with biallelic MYH mutations had more polyps than carriers of single mutations or MYH wild-type patients (medians, 55 v 3 v 7, respectively; p < 0.01). Four out of 28 (29%) patients with 15 to 115 adenomas had biallelic MYH mutations. All somatic APC mutations identified in such patients were the expected somatic G:C-→T:A transversions. No clearly pathogenic MTH1 or OGG1 germ line mutations were identified. Conclusions: The data provide strong evidence to show that individuals with two allelic MYH mutations are predisposed to a multiple adenoma phenotype. Progression to colorectal carcinoma occurs in some cases.


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