title: Germline susceptibility to colorectal cancer due to base-excision repair gene defects.
abstract: DNA repair is a key process in the maintenance of genome integrity. Here, we present a large, systematically collected population-based association study (2,239 cases; 1,845 controls) that explores the contribution to colorectal cancer incidence of inherited defects in base-excision repair (BER) genes. We show that biallelic MUTYH defects impart a 93-fold (95% CI 42-213) excess risk of colorectal cancer, which accounts for 0.8% of cases aged <55 years and 0.54% of the entire cohort. Penetrance for homozygous carriers was almost complete by age 60 years. Significantly more biallelic carriers had coexisting adenomatous polyps. However, notably, 36% of biallelic carriers had no polyps. Three patients with heterozygous MUTYH defects carried monoallelic mutations in other BER genes (OGG1 and MTH1). Recessive inheritance accounted for the elevated risk for those aged <55 years. However, there was also a 1.68-fold (95% CI 1.07-2.95) excess risk for heterozygous carriers aged >55 years, with a population attributable risk in this age group of 0.93% (95% CI 0%-2.0%). These data provide the strongest evidence to date for a causative role of BER defects in colorectal cancer etiology and show, to our knowledge for the first time, that heterozygous MUTYH mutations predispose to colorectal cancer later in life. These findings have clinical relevance for BER gene testing for patients with colorectal cancer and for genetic counseling of their relatives.
authors.affiliation: Colon Cancer Genetics Group, School of Clinical and Molecular Medicine, University of Edinburgh, United Kingdom. Susan.Farrington@hgu.mrc.ac.uk
authors.forename: Susan M
authors.initials: SM
authors.lastname: Farrington
authors.forename: Albert
authors.initials: A
authors.lastname: Tenesa
authors.forename: Rebecca
authors.initials: R
authors.lastname: Barnetson
authors.forename: Alice
authors.initials: A
authors.lastname: Wiltshire
authors.forename: James
authors.initials: J
authors.lastname: Prendergast
authors.forename: Mary
authors.initials: M
authors.lastname: Porteous
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Dunlop
mesh_terms: D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004198:Disease Susceptibility; D006579:Heterozygote; D006801:Humans; D007417:Intestinal Polyps / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D019683:Penetrance; D011159:Population Surveillance
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase