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

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.

Nature medicine. 2017 Mar 13 [Epub ahead of print]

Helen Davies, Dominik Glodzik, Sandro Morganella, Lucy R Yates, Johan Staaf, Xueqing Zou, Manasa Ramakrishna, Sancha Martin, Sandrine Boyault, Anieta M Sieuwerts, Peter T Simpson, Tari A King, Keiran Raine, Jorunn E Eyfjord, Gu Kong, Åke Borg, 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

Wellcome Trust Sanger Institute, Hinxton, UK., Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden., Translational Research Lab Department, Centre Léon Bérard, Lyon, France., Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics, Erasmus University Medical Center, Rotterdam, the Netherlands., Centre for Clinical Research and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia., Memorial Sloan Kettering Cancer Center, New York, New York, USA., Cancer Research Laboratory, Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea., European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK., Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen, the Netherlands., Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands., Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway., Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands., Department of Pathology, Institut Curie, Paris, France., Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium., Breast Cancer Now Research Unit, King's College, London, UK., Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium., Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA., Equipe Erable, INRIA Grenoble-Rhône-Alpes, Montbonnot-Saint Martin, France.