Association of Rad51 polymorphism with DNA repair in BRCA1 mutation carriers and sporadic breast cancer risk

BMC Cancer. 2011 Jun 27:11:278. doi: 10.1186/1471-2407-11-278.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • BRCA1 Protein / physiology*
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Cell Line, Transformed / radiation effects
  • Cell Line, Transformed / ultrastructure
  • Cells, Cultured / radiation effects
  • Cells, Cultured / ultrastructure
  • DNA Breaks*
  • DNA Repair / genetics
  • DNA Repair / physiology*
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / radiation effects*
  • Family Health
  • Female
  • Genes, BRCA1*
  • Genetic Predisposition to Disease
  • Haplotypes / genetics
  • Heterozygote
  • Humans
  • Lymphocytes / radiation effects
  • Lymphocytes / ultrastructure
  • Middle Aged
  • Mutagens / pharmacology
  • Mutation*
  • New York / epidemiology
  • Polymorphism, Single Nucleotide*
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / physiology*
  • Radiation Tolerance / genetics
  • Registries
  • Risk

Substances

  • BRCA1 Protein
  • DNA, Neoplasm
  • Mutagens
  • RAD51 protein, human
  • Rad51 Recombinase