Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer Academic Article uri icon


MeSH Major

  • BRCA1 Protein
  • BRCA2 Protein
  • Breast Neoplasms
  • DNA Repair-Deficiency Disorders
  • Rad51 Recombinase
  • Recombinational DNA Repair


  • Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole-exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumour-specific DNA repair defects. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

publication date

  • January 2017



  • Academic Article



  • eng

PubMed Central ID

  • PMC5516531

Digital Object Identifier (DOI)

  • 10.1002/path.4890

PubMed ID

  • 28299801

Additional Document Info