title: Association of Rad51 polymorphism with DNA repair in BRCA1 mutation carriers and sporadic breast cancer risk.
abstract: BACKGROUND
  Inter-individual variation in DNA repair capacity is thought to modulate breast cancer risk. The phenotypic mutagen sensitivity assay (MSA) measures DNA strand breaks in lymphocytes; women with familial and sporadic breast cancers have a higher mean number of breaks per cell (MBPC) than women without breast cancer. Here, we explore the relationships between the MSA and the Rad51 gene, which encodes a DNA repair enzyme that interacts with BRCA1 and BRCA2, in BRCA1 mutation carriers and women with sporadic breast cancer.
  
  
  METHODS
  Peripheral blood lymphoblasts from women with known BRCA1 mutations underwent the MSA (n = 138 among 20 families). BRCA1 and Rad51 genotyping and sequencing were performed to identify SNPs and haplotypes associated with the MSA. Positive associations from the study in high-risk families were subsequently examined in a population-based case-control study of breast cancer (n = 1170 cases and 2115 controls).
  
  
  RESULTS
  Breast cancer diagnosis was significantly associated with the MSA among women from BRCA1 families (OR = 3.2 95%CI: 1.5-6.7; p = 0.004). The Rad51 5'UTR 135 C>G genotype (OR = 3.64; 95% CI: 1.38, 9.54; p = 0.02), one BRCA1 haplotype (p = 0.03) and in a polygenic model, the E1038G and Q356R BRCA1 SNPs were significantly associated with MBPC (p = 0.009 and 0.002, respectively). The Rad51 5'UTR 135C genotype was not associated with breast cancer risk in the population-based study.
  
  
  CONCLUSIONS
  Mutagen sensitivity might be a useful biomarker of penetrance among women with BRCA1 mutations because the MSA phenotype is partially explained by genetic variants in BRCA1 and Rad51.
authors.affiliation: Howard University Cancer Center, 2041 Georgia Ave, NW Washington, DC 20060, USA. lricks-santi@howard.edu
authors.forename: Luisel J
authors.initials: LJ
authors.lastname: Ricks-Santi
authors.forename: Lara E
authors.initials: LE
authors.lastname: Sucheston
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Jo L
authors.initials: JL
authors.lastname: Freudenheim
authors.forename: Claudine J
authors.initials: CJ
authors.lastname: Isaacs
authors.forename: Marc D
authors.initials: MD
authors.lastname: Schwartz
authors.forename: Ramona G
authors.initials: RG
authors.lastname: Dumitrescu
authors.forename: Catalin
authors.initials: C
authors.lastname: Marian
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
authors.forename: Dominica
authors.initials: D
authors.lastname: Vito
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Edge
authors.forename: Peter G
authors.initials: PG
authors.lastname: Shields
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D002461:Cell Line, Transformed / Q000528:radiation effects / Q000648:ultrastructure; D002478:Cells, Cultured / Q000528:radiation effects / Q000648:ultrastructure; D053960:DNA Breaks; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004273:DNA, Neoplasm / Q000235:genetics / Q000528:radiation effects*; D005192:Family Health; D005260:Female; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008214:Lymphocytes / Q000528:radiation effects / Q000648:ultrastructure; D008875:Middle Aged; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D009518:New York / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D051135:Rad51 Recombinase / Q000235:genetics / Q000502:physiology*; D011836:Radiation Tolerance / Q000235:genetics; D012042:Registries; D012306:Risk
chemical_list: D019313:BRCA1 Protein; D004273:DNA, Neoplasm; D009153:Mutagens; C495153:RAD51 protein, human; D051135:Rad51 Recombinase