Bi‐allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer |
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Authors: | Robert W Mutter Nadeem Riaz Charlotte KY 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 Jiang William Lee Britta Weigelt Jorge S Reis‐Filho Simon N Powell |
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Affiliation: | 1. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA;2. Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA;3. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA;4. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA;5. Department of Radiation Oncology, Yale, New Haven, CT, USA;6. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA;7. Department of Systems Biology, Harvard Medical School, Boston, MA, USA |
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Abstract: | 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. |
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Keywords: | BRCAness homologous recombination‐deficient RAD51 DNA repair mutation |
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