Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes

Breast Cancer Res. 2014 Dec 5;16(6):475. doi: 10.1186/s13058-014-0475-x.


Introduction: Homologous recombination (HR) DNA repair is of clinical relevance in breast cancer. Three DNA-based homologous recombination deficiency (HRD) scores (HRD-loss of heterozygosity score (LOH), HRD-telomeric allelic imbalance score (TAI), and HRD-large-scale state transition score (LST)) have been developed that are highly correlated with defects in BRCA1/2, and are associated with response to platinum therapy in triple negative breast and ovarian cancer. This study examines the frequency of BRCA1/2 defects among different breast cancer subtypes, and the ability of the HRD scores to identify breast tumors with defects in the homologous recombination DNA repair pathway.

Methods: 215 breast tumors representing all ER/HER2 subtypes were obtained from commercial vendors. Next-generation sequencing based assays were used to generate genome wide SNP profiles, BRCA1/2 mutation screening, and BRCA1 promoter methylation data.

Results: BRCA1/2 deleterious mutations were observed in all breast cancer subtypes. BRCA1 promoter methylation was observed almost exclusively in triple negative breast cancer. BRCA1/2 deficient tumors were identified with BRCA1/2 mutations, or BRCA1 promoter methylation, and loss of the second allele of the affected gene. All three HRD scores were highly associated with BRCA1/2 deficiency (HRD-LOH: P = 1.3 × 10(-17); HRD-TAI: P = 1.5 × 10(-19); HRD-LST: P = 3.5 × 10(-18)). A combined score (HRD-mean) was calculated using the arithmetic mean of the three scores. In multivariable analyses the HRD-mean score captured significant BRCA1/2 deficiency information not captured by the three individual scores, or by clinical variables (P values for HRD-Mean adjusted for HRD-LOH: P = 1.4 × 10(-8); HRD-TAI: P = 2.9 × 10(-7); HRD-LST: P = 2.8 × 10(-8); clinical variables: P = 1.2 × 10(-16)).

Conclusions: The HRD scores showed strong correlation with BRCA1/2 deficiency regardless of breast cancer subtype. The frequency of elevated scores suggests that a significant proportion of all breast tumor subtypes may carry defects in the homologous recombination DNA repair pathway. The HRD scores can be combined to produce a more robust predictor of HRD. The combination of a robust score, and the FFPE compatible assay described in this study, may facilitate use of agents targeting homologous recombination DNA repair in the clinical setting.

MeSH terms

  • Allelic Imbalance
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • DNA Methylation
  • DNA Repair-Deficiency Disorders / genetics*
  • Female
  • Genes, BRCA1*
  • Genes, BRCA2*
  • Homologous Recombination
  • Humans
  • Logistic Models
  • Loss of Heterozygosity
  • Mutation
  • Promoter Regions, Genetic
  • Receptor, ErbB-2 / metabolism
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / metabolism


  • Receptors, Estrogen
  • Receptors, Progesterone
  • ERBB2 protein, human
  • Receptor, ErbB-2