title: ERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping.
abstract: The failure of linkage studies to identify further high-penetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk, as the most likely candidate. We have carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single-nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. In stage 1, genotype frequencies for 640 SNPs in 111 genes were compared between 864 breast cancer cases and 845 controls from the Spanish population. In stage 2, candidate SNPs identified in stage 1 (nominal P < 0.01) were tested in a Finnish series of 884 cases and 1,104 controls. Of the 10 candidate SNPs in seven genes identified in stage 1, one (rs744154) on intron 1 of ERCC4, a gene belonging to the nucleotide excision repair pathway, was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2 (odds ratio, 0.57; Bonferroni-adjusted P = 0.04). After considering potential functional SNPs in the region of high linkage disequilibrium that extends across the entire gene and upstream into the promoter region, we concluded that rs744154 itself could be causal. Although intronic, it is located on the first intron, in a region that is highly conserved across species, and could therefore be functionally important. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer.
authors.affiliation: National Genotyping Centre, Spanish National Cancer Centre, Madrid, Spain.
authors.forename: Roger Laughlin
authors.initials: RL
authors.lastname: Milne
authors.forename: Gloria
authors.initials: G
authors.lastname: Ribas
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.forename: Rainer
authors.initials: R
authors.lastname: Fagerholm
authors.forename: Antonio
authors.initials: A
authors.lastname: Salas
authors.forename: Emilio
authors.initials: E
authors.lastname: González
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D005387:Finland / Q000453:epidemiology; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D013030:Spain / Q000453:epidemiology
chemical_list: D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C095888:xeroderma pigmentosum group F protein