TY - JOUR T1 - Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3 JF - Gut JO - Gut DO - 10.1136/gut.2007.145748 AU - Anthony R Dallosso AU - Sunil Dolwani AU - Natalie Jones AU - Sian Jones AU - James Colley AU - Julie Maynard AU - Shelley Idziaszczyk AU - Vikki Humphreys AU - Julie Arnold AU - Alan Donaldson AU - Diana Eccles AU - Anthony Ellis AU - D. Gareth Evans AU - Ian M. Frayling AU - Frederik J. Hes AU - Richard S. Houlston AU - Eamonn R. Maher AU - Maartje Nielsen AU - Susan Parry AU - Emma Tyler AU - Valentina Moskvina AU - Jeremy P. Cheadle AU - Julian R. Sampson Y1 - 2008/05/30 UR - http://gut.bmj.com/content/early/2008/05/30/gut.2007.145748.abstract N2 - Background: MUTYH associated polyposis (MAP) is a recessive trait characterised by multiple colorectal adenomas and a high risk of colorectal cancer. MUTYH functions in the DNA base excision repair pathway and has a key role in the repair of oxidative DNA damage. Objectives: To assess the contribution of inherited variants in genes involved in base excision repair and oxidative DNA damage including MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 to the multiple colorectal adenoma phenotype. Methods: Inherited variants of MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 were sought in 167 unrelated patients with multiple colorectal adenomas whose family histories were consistent with recessive inheritance. We also characterised these variants in ~ 300 population controls. Results: Thirty three patients (20%) and no controls were MUTYH homozygotes or compound heterozygotes (i.e. carried two mutations) and therefore had MAP. Eight different pathogenic MUTYH mutations were identified of which 4 were novel. MAP cases had significantly more adenomas than non-MAP cases (P=0.0009; Exact test for trends in proportions) and presented earlier (P=0.013; ANOVA). Twenty four protein altering variants were identified upon screening of OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1. However, all combinations of two (or more) variants that were identified at an individual locus in patients were also seen in controls and no variants were significantly over (or under-) represented in cases. Conclusion: Multiple rare alleles of MUTYH are associated with autosomal recessive MUTYH Associated Polyposis (MAP) whilst OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 do not contribute significantly to autosomal recessive polyposis. ER -