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


Authors: Mutter, R. W.; Riaz, N.; Ng, C. K. Y.; Delsite, R.; Piscuoglio, S.; Edelweiss, M.; Martelotto, L. G.; Sakr, R. A.; King, T. A.; Giri, D. D.; Drobnjak, M.; Brogi, E.; Bindra, R.; Bernheim, G.; Lim, R. S.; Blecua, P.; Desrichard, A.; Higginson, D.; Towers, R.; Jiang, R.; Lee, W.; Weigelt, B.; Reis-Filho, J. S.; Powell, S. N.
Article Title: Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer
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. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Keywords: mutation; dna repair; rad51; brcaness; homologous recombination-deficient
Journal Title: Journal of Pathology
Volume: 242
Issue: 2
ISSN: 0022-3417
Publisher: Wiley Blackwell  
Date Published: 2017-06-01
Start Page: 165
End Page: 177
Language: English
DOI: 10.1002/path.4890
PROVIDER: scopus
PUBMED: 28299801
PMCID: PMC5516531
DOI/URL:
Notes: Marija Drobnjak's name is misspelled on the original publication -- Article -- Export Date: 3 July 2017 -- Source: Scopus
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MSK Authors
  1. Simon Nicholas Powell
    300 Powell
  2. Dilip D Giri
    180 Giri
  3. Nadeem Riaz
    374 Riaz
  4. Tari King
    186 King
  5. Ranjit Singh Bindra
    9 Bindra
  6. Robert Wesley Mutter
    17 Mutter
  7. Rita Sakr
    61 Sakr
  8. Marcia Edelweiss
    100 Edelweiss
  9. Edi Brogi
    480 Brogi
  10. Robert Lee Delsite
    11 Delsite
  11. Russell Towers
    13 Towers
  12. William Lee
    38 Lee
  13. Britta Weigelt
    544 Weigelt
  14. Kiu Yan Charlotte Ng
    155 Ng
  15. Raymond Sear Lim
    56 Lim