title: MUTYH-associated polyposis--from defect in base excision repair to clinical genetic testing.
abstract: Established predisposition genes account for only a small proportion of familial colorectal cancer. Recently, it has been shown that germline mutations in MUTYH predispose to MUTYH-associated polyposis (MAP), an autosomal recessive disorder characterised by multiple colorectal adenomas and carcinomas. MUTYH functions as a base excision repair DNA glycosylase that excises adenines misincorporated opposite 8-oxo-7,8-dihydro-2'-deoxyguanosine, one of the most stable products of oxidative DNA damage. It is the failure to correct this mispair that is thought to give rise to the characteristic signature of G:C-->T:A mutations found in MAP-associated tumours. Here, we review the germline mutation spectrum at the MUTYH locus (comprising 30 truncating and 55 missense/inframe insertion/deletion variants) and the molecular mechanism and biochemical defect(s) underlying this disorder. We also discuss the application of molecular genetic analysis of MUTYH in clinical practice.
authors.affiliation: Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. cheadlejp@cardiff.ac.uk
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
mesh_terms: D000236:Adenoma / Q000175:diagnosis / Q000235:genetics; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D044483:Intestinal Polyposis / Q000175:diagnosis* / Q000235:genetics*; D020125:Mutation, Missense
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase