title: Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis.
abstract: Biallelic inherited mutations in the oxidative DNA damage repair gene MUTYH predispose to colorectal adenomas and colorectal carcinoma (CRC) with high penetrance. We investigated whether rare inherited variants in other oxidative DNA damage repair genes predisposed to CRC. Single marker association analyses were assessed under an allelic model with Bonferroni correction for multiple testing. All statistical tests were two-sided. A rare inherited nonsynonymous variant in OGG1 (Gly308Glu), the functional partner of MUTYH, was over-represented in case patients with advanced CRC compared with population-based control subjects (n = 36 of 2142 case patients vs n = 15 of 2175 control subjects in the training phase, P = 1.8×10(-3); and n = 22 of 1005 case patients vs n = 8 of 1389 control subjects in the validation phase, P = 4.8×10(-4); P = 1.4×10(-5) combined; odds ratio = 2.92, 95% confidence interval = 1.80 to 4.74). Glycine at residue 308 was highly conserved through evolution, and the glutamic acid substitution was predicted as likely to interfere with function. Biallelic inherited and somatic OGG1 mutations were rarely observed in OGG1 (Gly308Glu) carriers, nor did we find any associated somatic mutator phenotype. These data suggest that OGG1 (Gly308Glu) may act as a low-penetrance allele that contributes to colorectal tumorigenesis.
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Smith
authors.forename: Hannah
authors.initials: H
authors.lastname: West
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harris
authors.forename: Shelley
authors.initials: S
authors.lastname: Idziaszczyk
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Maughan
authors.forename: Richard
authors.initials: R
authors.lastname: Kaplan
authors.forename: Susan
authors.initials: S
authors.lastname: Richman
authors.forename: Philip
authors.initials: P
authors.lastname: Quirke
authors.forename: Matthew
authors.initials: M
authors.lastname: Seymour
authors.forename: Valentina
authors.initials: V
authors.lastname: Moskvina
authors.forename: Verena
authors.initials: V
authors.lastname: Steinke
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.forename: Juul
authors.initials: J
authors.lastname: Wijnen
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002277:Carcinoma / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018698:Glutamic Acid; D005998:Glycine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D010084:Oxidation-Reduction; D019683:Penetrance; D015854:Up-Regulation
chemical_list: D018698:Glutamic Acid; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; C479058:oxoguanine glycosylase 1, human; D005998:Glycine