Germline susceptibility to colorectal cancer due to base-excision repair gene defects

Am J Hum Genet. 2005 Jul;77(1):112-9. doi: 10.1086/431213. Epub 2005 May 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cohort Studies
  • Colorectal Neoplasms / genetics*
  • DNA Glycosylases / genetics*
  • DNA Repair / genetics*
  • Disease Susceptibility
  • Heterozygote
  • Humans
  • Intestinal Polyps / genetics
  • Middle Aged
  • Mutation*
  • Penetrance
  • Population Surveillance


  • DNA Glycosylases
  • mutY adenine glycosylase