title: HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Dominik
authors.initials: D
authors.lastname: Glodzik
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Sandro
authors.initials: S
authors.lastname: Morganella
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.|Guy's and St Thomas' NHS Trust, London, UK.
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Yates
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Zou
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.|Oncology, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Little Chesterford, UK.
authors.forename: Manasa
authors.initials: M
authors.lastname: Ramakrishna
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Sancha
authors.initials: S
authors.lastname: Martin
authors.affiliation: Translational Research Lab Department, Centre Léon Bérard, Lyon, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Boyault
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Anieta M
authors.identifier: http://orcid.org/0000-0003-1341-5400
authors.initials: AM
authors.lastname: Sieuwerts
authors.affiliation: Centre for Clinical Research and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Simpson
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Tari A
authors.initials: TA
authors.lastname: King
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Keiran
authors.identifier: http://orcid.org/0000-0002-5634-1539
authors.initials: K
authors.lastname: Raine
authors.affiliation: Cancer Research Laboratory, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Jorunn E
authors.initials: JE
authors.lastname: Eyfjord
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Ewan
authors.initials: E
authors.lastname: Birney
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: van de Vijver
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: John W M
authors.identifier: http://orcid.org/0000-0002-3428-3366
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.affiliation: Centre for Clinical Research and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
authors.affiliation: Department of Pathology, Institut Curie, Paris, France.|INSERM U934, Institut Curie, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium.
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.affiliation: Breast Cancer Now Research Unit, King's College, London, UK.|Breast Cancer Now Toby Robin's Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Andrew
authors.identifier: http://orcid.org/0000-0001-8715-2901
authors.initials: A
authors.lastname: Tutt
authors.affiliation: Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
authors.affiliation: Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.|HistoGeneX, Wilrijk, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Van Laere
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: Equipe Erable, INRIA Grenoble-Rhône-Alpes, Montbonnot-Saint Martin, France.|Synergie Lyon Cancer, Centre Léon Bérard, Lyon, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Viari
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.|East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
mesh_terms: D019540:Area Under Curve; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics*; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors