title: Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations.
abstract: We have recently demonstrated that inherited defects of the base excision repair gene MYH predispose to multiple colorectal adenomas and carcinoma. Three affected siblings from a single British family were identified as Y165C/G382D compound heterozygotes and both missense mutations were shown to be functionally compromised. Here, we report the identification of seven further unrelated patients with >100 colorectal adenomas (six with colorectal cancer) and biallelic germline mutations in MYH: four were homozygous for truncating mutations, two were homozygous for Y165C and one was a Y165C/G382D compound heterozygote. As predicted from studies of the bacterial and yeast orthologues of MYH, colorectal tumours from affected individuals displayed a significant excess of somatic G:C-->T:A mutations in APC, as compared to sporadic ( chi(2)=242.96, P<10(-20)) or FAP-associated ( chi(2)=194.85, P<10(-20)) colorectal tumours. The sequence immediately downstream of the somatic G:C-->T:A mutations was predominantly AA, irrespective of the nature of the germline MYH mutations. These findings confirm the role of MYH in colorectal adenoma and carcinoma predisposition.
authors.affiliation: Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Paul
authors.initials: P
authors.lastname: Emmerson
authors.forename: Julie
authors.initials: J
authors.lastname: Maynard
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Best
authors.forename: Sheila
authors.initials: S
authors.lastname: Jordan
authors.forename: Geraint T
authors.initials: GT
authors.lastname: Williams
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000483:Alleles; D002851:Chromatography, High Pressure Liquid; D003062:Codon; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D009699:N-Glycosyl Hydrolases / Q000235:genetics*; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: D003062:Codon; D004273:DNA, Neoplasm; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C061738:mutY adenine glycosylase