title: Investigation of the effects of DNA repair gene polymorphisms on the risk of colorectal cancer.
abstract: Despite their prime candidate status, polymorphisms near genes involved in DNA repair or in other functions related to genome stability have been conspicuously under-represented in the significant associations reported from genome-wide association studies (GWAS) of cancer susceptibility. In this study, we assessed a set of single-nucleotide polymorphisms (SNPs) near 157 DNA repair genes in three colorectal cancer (CRC) GWAS. Although no individual SNP showed evidence of association, the set of SNPs as a whole was associated with colorectal cancer risk. When candidate SNPs were examined, our data did not support most of the previously reported associations with CRC susceptibility, an exception being an effect of the MLH1 promoter SNP -93G>A (rs1800734). Rare variants in CHEK2 (I157T and possibly del1100C) also appear to be associated with CRC risk. Overall, the absence to date of disease-associated DNA repair SNPs in cancer GWAS may be explained by a combination of the following: (i) many loci with individually very small effects on risk; (ii) rare alleles of moderate effect and (iii) subgroups of CRC, such as those with microsatellite instability, associated with specific variants. It will be particularly intriguing to determine whether any GWAS across cancer types identify DNA variants that predispose to cancers of more than one site.
authors.affiliation: Molecular and Population Genetics Laboratory and Oxford NIHR Comprehensive Biomedical Research Centre, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. iant@well.ox.ac.uk
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Sieber
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Dunlop
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D053842:Microsatellite Instability; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
chemical_list: D045643:DNA Repair Enzymes