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

Robert W. Mutter, Nadeem Riaz, Charlotte K.Y. Ng, Rob Delsite, Salvatore Piscuoglio, Marcia Edelweiss, Luciano G. 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

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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 (US)
Pages (from-to)165-177
Number of pages13
JournalJournal of Pathology
Issue number2
StatePublished - Jun 2017


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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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