Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer

Robert W Mutter, Nadeem Riaz, Charlotte KY Ng, Rob Delsite, Salvatore Piscuglio, Marcia Edelweiss, Luciano Gaston Martelotto, Rita A. Sakr, Tari A. King, Dilip D Giri, Maria Drobnjak, Edi Brogi, Ranjit Bindra, Giana Bernheim, Raymond S. Lim, Pedro Blecua, Alexis Desrichard, Dan Higginson, Russell Towers, Ruomu JiangWilliam Lee, Britta Weigelt, Jorge S. Reis-Filho, Simon N Powell

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20 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)165-177
Number of pages13
JournalJournal of Pathology
Issue number2
Publication statusPublished - 1 Jun 2017
Externally publishedYes


  • BRCAness
  • DNA repair
  • homologous recombination-deficient
  • mutation
  • RAD51

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