HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures

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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.


  • Helen R. Davies
  • Dominik Glodzik
  • Sandro Morganella
  • Lucy R. Yates
  • Xueqing Zou
  • Manasa Ramakrishna
  • Sancha Martin
  • Sandrine Boyault
  • Anieta M. Sieuwerts
  • Peter T Simpson
  • Tari A King
  • Keiran Raine
  • Jorunn E. Eyfjord
  • Gu Kong
  • Ewan Birney
  • Hendrik G. Stunnenberg
  • Marc J van de Vijver
  • Anne-Lise Børresen-Dale
  • John W. M. Martens
  • Paul N. Span
  • Sunil R. Lakhani
  • Anne Vincent-Salomon
  • Christos Sotiriou
  • Andrew Tutt
  • Alastair M Thompson
  • Steven Van Laere
  • Andrea L. Richardson
  • Alain Viari
  • Peter J. Campbell
  • Michael R. Stratton
  • Serena Nik-Zainal
External organisations
  • Wellcome Trust Sanger Institute
  • Guy's and St Thomas' NHS Foundation Trust
  • Centre Léon Bérard
  • Erasmus University Rotterdam
  • University of Queensland
  • Memorial Sloan-Kettering Cancer Center
  • University of Iceland
  • Hanyang University
  • European Bioinformatics Institute
  • Radboud University Nijmegen
  • Academic Medical Center of University of Amsterdam (AMC)
  • University of Oslo
  • Radboud University Medical Center
  • Royal Brisbane and Women's Hospital
  • Curie Institute, Paris
  • Free University of Brussels (ULB)
  • Institute of Cancer Research London
  • University of Texas
  • HistoGeneX NV
  • Dana-Farber Cancer Institute
  • Cambridge University Hospitals NHS Foundation Trust
  • AstraZeneca, UK
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)517-525
Number of pages9
JournalNature Medicine
Issue number4
Publication statusPublished - 2017 Apr
Publication categoryResearch

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