Abstract

Approximately 1–5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (1–5%) who could have selective therapeutic sensitivity to PARP inhibition.

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Acknowledgements

This work has been performed on data that were previously published. They were generated and funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (BASIS), a European research project funded by the European Community's Seventh Framework Programme (FP7/2010-2014) under grant agreement number 242006; the Triple Negative project funded by the Wellcome Trust (grant reference 077012/Z/05/Z) and the HER2+ project funded by Institut National du Cancer (INCa) in France (grants 226-2009, 02-2011, 41-2012, 144-2008, 06-2012). The ICGC Asian Breast Cancer Project was funded through a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111218-SC01). The Oslo Breast Cancer Research Consortium (OSBREAC), Norway (http://www.osbreac.no/), contributed samples to the study. D.G. was supported by the EU-FP7-SUPPRESSTEM project. A.L.R. is partially supported by the Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer (NIH/NCI 5 P50 CA168504-02). A.S. was supported by Cancer Genomics Netherlands (CGC.nl) through a grant from the Netherlands Organisation of Scientific research (NWO). C.S. is supported by a grant from the Breast Cancer Research Foundation. E.B. was funded by EMBL. A.T. acknowledges infrastructure support funding from the NIHR Biomedical Research Centres at Guy's and St Thomas' and Royal Marsden Hospital NHS Foundation Trusts. G.K. is supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (NRF 2015R1A2A1A10052578). S.N.-Z. is a Wellcome Beit Fellow and personally funded by a Wellcome Trust Intermediate Fellowship (WT100183MA). Finally, we would like to acknowledge all members of the ICGC Breast Cancer Working Group and ICGC Asian Breast Cancer Project, for without the foresight of engaging in this scale of collaboration we would not have gained these insights.

Author information

Author notes

    • Helen Davies
    •  & Dominik Glodzik

    These authors contributed equally to this work.

Affiliations

  1. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Helen Davies
    • , Dominik Glodzik
    • , Sandro Morganella
    • , Lucy R Yates
    • , Xueqing Zou
    • , Manasa Ramakrishna
    • , Sancha Martin
    • , Keiran Raine
    • , Peter J Campbell
    • , Michael R Stratton
    •  & Serena Nik-Zainal
  2. Guy's and St Thomas' NHS Trust, London, UK.

    • Lucy R Yates
  3. Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

    • Johan Staaf
    •  & Åke Borg
  4. Oncology, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Little Chesterford, UK.

    • Manasa Ramakrishna
  5. Translational Research Lab Department, Centre Léon Bérard, Lyon, France.

    • Sandrine Boyault
  6. Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Anieta M Sieuwerts
    •  & John W M Martens
  7. Centre for Clinical Research and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.

    • Peter T Simpson
    •  & Sunil R Lakhani
  8. Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Tari A King
  9. Cancer Research Laboratory, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Jorunn E Eyfjord
  10. Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea.

    • Gu Kong
  11. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Ewan Birney
  12. Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen, the Netherlands.

    • Hendrik G Stunnenberg
  13. Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands.

    • Marc J van de Vijver
  14. Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

    • Anne-Lise Børresen-Dale
  15. K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.

    • Anne-Lise Børresen-Dale
  16. Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Paul N Span
  17. Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Paul N Span
  18. Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

    • Sunil R Lakhani
  19. Department of Pathology, Institut Curie, Paris, France.

    • Anne Vincent-Salomon
  20. INSERM U934, Institut Curie, Paris, France.

    • Anne Vincent-Salomon
  21. Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium.

    • Christos Sotiriou
  22. Breast Cancer Now Research Unit, King's College, London, UK.

    • Andrew Tutt
  23. Breast Cancer Now Toby Robin's Research Centre, Institute of Cancer Research, London, UK.

    • Andrew Tutt
  24. Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Alastair M Thompson
  25. Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

    • Steven Van Laere
  26. HistoGeneX, Wilrijk, Belgium.

    • Steven Van Laere
  27. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Andrea L Richardson
  28. Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Andrea L Richardson
  29. Equipe Erable, INRIA Grenoble-Rhône-Alpes, Montbonnot-Saint Martin, France.

    • Alain Viari
  30. Synergie Lyon Cancer, Centre Léon Bérard, Lyon, France.

    • Alain Viari
  31. East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

    • Serena Nik-Zainal

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Contributions

H.D., D.G. and S.N.-Z. drove the development of the intellectual concepts, performed analyses and wrote the manuscript. S. Morganella, J.S., X.Z. and M.R. contributed towards data curation and performed analyses. L.R.Y., S.B., A.M.S., P.T.S., T.A.K., J.E.E., P.N.S., S.R.L., A.V.-S., C.S., A.T., A.M.T. and S.V.L. contributed new samples and/or to experimental design of the study. S. Martin was the scientific project coordinator. K.R. provided bioinformatics support. P.J.C. provided infrastructure at the Wellcome Trust Sanger Institute. G.K., A.B., E.B., H.G.S., M.J.v.d.V., A.-L.B.-D., J.W.M.M., A.M.T., A.L.R., A.V. and M.R.S. originally conceived the concept of the Breast Cancer Consortium that generated the data resource that has been utilized for these analyses, contributed old and new samples, and contributed comments towards the manuscript.

Competing interests

H. Davies, D. Glodzik and S. Nik-Zainal are inventors on a patent application encompassing the code and intellectual principle on this algorithm. The patent has been filed with UK IPO. A.T. has been in receipt of payments from the Institute of Cancer Research Rewards to inventors scheme associated with the invention of PARP inhibitors as therapy for BRCA1- and BRCA2–mutation-associated cancers.

Corresponding author

Correspondence to Serena Nik-Zainal.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures and Text

    Supplementary Figures 1–9, Supplementary Note and Supplementary Tables 10–14

Excel files

  1. 1.

    Supplementary Table 1

    560 Breast cancer whole genomes

  2. 2.

    Supplementary Table 2

    Results from learning using 22 previously known BRCA1 and BRCA2 germline null samples

  3. 3.

    Supplementary Table 3

    Results from HRDectect predictor trained with 77 BRCA1- and BRCA2-germline-null samples

  4. 4.

    Supplementary Table 4

    Details of mutations in selected genes in 560 breast cancers

  5. 5.

    Supplementary Table 5

    Additional breast cancer whole genomes

  6. 6.

    Supplementary Table 6

    560 breast cancer whole genomes down-sampled to 10X coverage

  7. 7.

    Supplementary Table 7

    Data representing whole exome sequencing in 560 breast cancer samples

  8. 8.

    Supplementary Table 8

    Ovarian and pancreatic whole genomes

  9. 9.

    Supplementary Table 9

    Whole genome sequencing of single FFPE breast cancer sample and 9 breast cancer samples treated with neoadjuvant anthracyclines

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https://doi.org/10.1038/nm.4292

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