title: Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2.
abstract: BACKGROUND
  Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2.
  
  
  METHODS
  Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers.
  
  
  RESULTS
  An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2.
  
  
  CONCLUSIONS
  No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.
authors.affiliation: Human Genetics Group, Spanish National Cancer Centre, C/Melchor Fernández Almagro 3, 28029 Madrid, Spain. aosorio@cnio.es
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D002277:Carcinoma / Q000453:epidemiology / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004843:Epistasis, Genetic / Q000502:physiology*; D005260:Female; D017144:Focus Groups; D019398:Genes, BRCA1 / Q000502:physiology; D024522:Genes, BRCA2 / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000076105:X-ray Repair Cross Complementing Protein 1; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human