HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.
Identifieur interne : 000B12 ( Main/Exploration ); précédent : 000B11; suivant : 000B13HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.
Auteurs : Helen Davies [Royaume-Uni] ; Dominik Glodzik [Royaume-Uni] ; Sandro Morganella [Royaume-Uni] ; Lucy R. Yates [Royaume-Uni] ; Johan Staaf [Suède] ; Xueqing Zou [Royaume-Uni] ; Manasa Ramakrishna [Royaume-Uni] ; Sancha Martin [Royaume-Uni] ; Sandrine Boyault [France] ; Anieta M. Sieuwerts [Pays-Bas] ; Peter T. Simpson [Australie] ; Tari A. King [États-Unis] ; Keiran Raine [Royaume-Uni] ; Jorunn E. Eyfjord [Islande] ; Gu Kong [Corée du Sud] ; Ke Borg [Suède] ; Ewan Birney [Royaume-Uni] ; Hendrik G. Stunnenberg [Pays-Bas] ; Marc J. Van De Vijver [Pays-Bas] ; Anne-Lise B Rresen-Dale [Norvège] ; John W M. Martens [Pays-Bas] ; Paul N. Span [Pays-Bas] ; Sunil R. Lakhani [Australie] ; Anne Vincent-Salomon [France] ; Christos Sotiriou [Belgique] ; Andrew Tutt [Royaume-Uni] ; Alastair M. Thompson [États-Unis] ; Steven Van Laere [Belgique] ; Andrea L. Richardson [États-Unis] ; Alain Viari [France] ; Peter J. Campbell [Royaume-Uni] ; Michael R. Stratton [Royaume-Uni] ; Serena Nik-Zainal [Royaume-Uni]Source :
- Nature medicine [ 1546-170X ] ; 2017.
Descripteurs français
- KwdFr :
- Aire sous la courbe, Analyse de mutations d'ADN, Femelle, Humains, Inhibiteurs de poly(ADP-ribose) polymérases (usage thérapeutique), Modèles génétiques, Modèles logistiques, Mutation, Mâle, Protéine BRCA1 (déficit), Protéine BRCA1 (génétique), Protéine BRCA2 (déficit), Protéine BRCA2 (génétique), Tumeur du sein de l'homme (génétique), Tumeurs de l'ovaire (génétique), Tumeurs de l'ovaire (traitement médicamenteux), Tumeurs du pancréas (génétique), Tumeurs du pancréas (traitement médicamenteux), Tumeurs du sein (génétique), Tumeurs du sein (traitement médicamenteux).
- MESH :
- déficit : Protéine BRCA1, Protéine BRCA2.
- génétique : Protéine BRCA1, Protéine BRCA2, Tumeur du sein de l'homme, Tumeurs de l'ovaire, Tumeurs du pancréas, Tumeurs du sein.
- traitement médicamenteux : Tumeurs de l'ovaire, Tumeurs du pancréas, Tumeurs du sein.
- usage thérapeutique : Inhibiteurs de poly(ADP-ribose) polymérases.
- Aire sous la courbe, Analyse de mutations d'ADN, Femelle, Humains, Modèles génétiques, Modèles logistiques, Mutation, Mâle.
English descriptors
- KwdEn :
- Area Under Curve, BRCA1 Protein (deficiency), BRCA1 Protein (genetics), BRCA2 Protein (deficiency), BRCA2 Protein (genetics), Breast Neoplasms (drug therapy), Breast Neoplasms (genetics), Breast Neoplasms, Male (genetics), DNA Mutational Analysis, Female, Humans, Logistic Models, Male, Models, Genetic, Mutation, Ovarian Neoplasms (drug therapy), Ovarian Neoplasms (genetics), Pancreatic Neoplasms (drug therapy), Pancreatic Neoplasms (genetics), Poly(ADP-ribose) Polymerase Inhibitors (therapeutic use).
- MESH :
- chemical , deficiency : BRCA1 Protein, BRCA2 Protein.
- chemical , genetics : BRCA1 Protein, BRCA2 Protein.
- drug therapy : Breast Neoplasms, Ovarian Neoplasms, Pancreatic Neoplasms.
- genetics : Breast Neoplasms, Breast Neoplasms, Male, Ovarian Neoplasms, Pancreatic Neoplasms.
- chemical , therapeutic use : Poly(ADP-ribose) Polymerase Inhibitors.
- Area Under Curve, DNA Mutational Analysis, Female, Humans, Logistic Models, Male, Models, Genetic, Mutation.
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.
DOI: 10.1038/nm.4292
PubMed: 28288110
Affiliations:
- Australie, Belgique, Corée du Sud, France, Islande, Norvège, Pays-Bas, Royaume-Uni, Suède, États-Unis
- Angleterre, Auvergne-Rhône-Alpes, Grand Londres, Gueldre, Hollande-Méridionale, Hollande-Septentrionale, Massachusetts, Province d'Anvers, Rhône-Alpes, Région capitale de Séoul, Région de Bruxelles-Capitale, Région flamande, Texas, État de New York, Île-de-France, Østlandet
- Amsterdam, Anvers, Bruxelles, Londres, Lyon, Nimègue, Oslo, Paris, Rotterdam, Séoul
- Université d'Anvers, Université libre de Bruxelles
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Le document en format XML
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Van De Vijver</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Pathology, Academic Medical Center, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></affiliation></author><author><name sortKey="B Rresen Dale, Anne Lise" sort="B Rresen Dale, Anne Lise" uniqKey="B Rresen Dale A" first="Anne-Lise" last="B Rresen-Dale">Anne-Lise B Rresen-Dale</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</region></placeName></affiliation></author><author><name sortKey="Martens, John W M" sort="Martens, John W M" uniqKey="Martens J" first="John W M" last="Martens">John W M. Martens</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics, Erasmus University Medical Center, Rotterdam, the Netherlands.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics, Erasmus University Medical Center, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Span, Paul N" sort="Span, Paul N" uniqKey="Span P" first="Paul N" last="Span">Paul N. Span</name><affiliation wicri:level="3"><nlm:affiliation>Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Radiation Oncology, Radboud University Medical Center, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R" last="Lakhani">Sunil R. Lakhani</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Clinical Research and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Clinical Research and School of Medicine, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Vincent Salomon, Anne" sort="Vincent Salomon, Anne" uniqKey="Vincent Salomon A" first="Anne" last="Vincent-Salomon">Anne Vincent-Salomon</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Institut Curie, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Pathology, Institut Curie, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Sotiriou, Christos" sort="Sotiriou, Christos" uniqKey="Sotiriou C" first="Christos" last="Sotiriou">Christos Sotiriou</name><affiliation wicri:level="4"><nlm:affiliation>Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region><settlement type="city">Bruxelles</settlement></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation></author><author><name sortKey="Tutt, Andrew" sort="Tutt, Andrew" uniqKey="Tutt A" first="Andrew" last="Tutt">Andrew Tutt</name><affiliation wicri:level="3"><nlm:affiliation>Breast Cancer Now Research Unit, King's College, London, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Breast Cancer Now Research Unit, King's College, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Thompson, Alastair M" sort="Thompson, Alastair M" uniqKey="Thompson A" first="Alastair M" last="Thompson">Alastair M. Thompson</name><affiliation wicri:level="2"><nlm:affiliation>Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Van Laere, Steven" sort="Van Laere, Steven" uniqKey="Van Laere S" first="Steven" last="Van Laere">Steven Van Laere</name><affiliation wicri:level="4"><nlm:affiliation>Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region>Région flamande</region><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation></author><author><name sortKey="Richardson, Andrea L" sort="Richardson, Andrea L" uniqKey="Richardson A" first="Andrea L" last="Richardson">Andrea L. Richardson</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Viari, Alain" sort="Viari, Alain" uniqKey="Viari A" first="Alain" last="Viari">Alain Viari</name><affiliation wicri:level="1"><nlm:affiliation>Equipe Erable, INRIA Grenoble-Rhône-Alpes, Montbonnot-Saint Martin, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Equipe Erable, INRIA Grenoble-Rhône-Alpes, Montbonnot-Saint Martin</wicri:regionArea><wicri:noRegion>Montbonnot-Saint Martin</wicri:noRegion><wicri:noRegion>Montbonnot-Saint Martin</wicri:noRegion></affiliation></author><author><name sortKey="Campbell, Peter J" sort="Campbell, Peter J" uniqKey="Campbell P" first="Peter J" last="Campbell">Peter J. Campbell</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R" last="Stratton">Michael R. Stratton</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Nik Zainal, Serena" sort="Nik Zainal, Serena" uniqKey="Nik Zainal S" first="Serena" last="Nik-Zainal">Serena Nik-Zainal</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28288110</idno><idno type="pmid">28288110</idno><idno type="doi">10.1038/nm.4292</idno><idno type="wicri:Area/PubMed/Corpus">000E57</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000E57</idno><idno type="wicri:Area/PubMed/Curation">000E54</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000E54</idno><idno type="wicri:Area/PubMed/Checkpoint">000E54</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000E54</idno><idno type="wicri:Area/Ncbi/Merge">004454</idno><idno type="wicri:Area/Ncbi/Curation">004454</idno><idno type="wicri:Area/Ncbi/Checkpoint">004454</idno><idno type="wicri:Area/Main/Merge">000B07</idno><idno type="wicri:Area/Main/Curation">000B12</idno><idno type="wicri:Area/Main/Exploration">000B12</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.</title><author><name sortKey="Davies, Helen" sort="Davies, Helen" uniqKey="Davies H" first="Helen" last="Davies">Helen Davies</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Glodzik, Dominik" sort="Glodzik, Dominik" uniqKey="Glodzik D" first="Dominik" last="Glodzik">Dominik Glodzik</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Morganella, Sandro" sort="Morganella, Sandro" uniqKey="Morganella S" first="Sandro" last="Morganella">Sandro Morganella</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Yates, Lucy R" sort="Yates, Lucy R" uniqKey="Yates L" first="Lucy R" last="Yates">Lucy R. Yates</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Staaf, Johan" sort="Staaf, Johan" uniqKey="Staaf J" first="Johan" last="Staaf">Johan Staaf</name><affiliation wicri:level="1"><nlm:affiliation>Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></affiliation></author><author><name sortKey="Zou, Xueqing" sort="Zou, Xueqing" uniqKey="Zou X" first="Xueqing" last="Zou">Xueqing Zou</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Ramakrishna, Manasa" sort="Ramakrishna, Manasa" uniqKey="Ramakrishna M" first="Manasa" last="Ramakrishna">Manasa Ramakrishna</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Martin, Sancha" sort="Martin, Sancha" uniqKey="Martin S" first="Sancha" last="Martin">Sancha Martin</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Boyault, Sandrine" sort="Boyault, Sandrine" uniqKey="Boyault S" first="Sandrine" last="Boyault">Sandrine Boyault</name><affiliation wicri:level="3"><nlm:affiliation>Translational Research Lab Department, Centre Léon Bérard, Lyon, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Translational Research Lab Department, Centre Léon Bérard, Lyon</wicri:regionArea><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Rhône-Alpes</region><settlement type="city">Lyon</settlement></placeName></affiliation></author><author><name sortKey="Sieuwerts, Anieta M" sort="Sieuwerts, Anieta M" uniqKey="Sieuwerts A" first="Anieta M" last="Sieuwerts">Anieta M. Sieuwerts</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics, Erasmus University Medical Center, Rotterdam, the Netherlands.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics, Erasmus University Medical Center, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Simpson, Peter T" sort="Simpson, Peter T" uniqKey="Simpson P" first="Peter T" last="Simpson">Peter T. Simpson</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Clinical Research and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Clinical Research and School of Medicine, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="King, Tari A" sort="King, Tari A" uniqKey="King T" first="Tari A" last="King">Tari A. King</name><affiliation wicri:level="2"><nlm:affiliation>Memorial Sloan Kettering Cancer Center, New York, New York, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Memorial Sloan Kettering Cancer Center, New York, New York</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Raine, Keiran" sort="Raine, Keiran" uniqKey="Raine K" first="Keiran" last="Raine">Keiran Raine</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Eyfjord, Jorunn E" sort="Eyfjord, Jorunn E" uniqKey="Eyfjord J" first="Jorunn E" last="Eyfjord">Jorunn E. Eyfjord</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Research Laboratory, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.</nlm:affiliation><country xml:lang="fr">Islande</country><wicri:regionArea>Cancer Research Laboratory, Faculty of Medicine, University of Iceland, Reykjavik</wicri:regionArea><wicri:noRegion>Reykjavik</wicri:noRegion></affiliation></author><author><name sortKey="Kong, Gu" sort="Kong, Gu" uniqKey="Kong G" first="Gu" last="Kong">Gu Kong</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Pathology, College of Medicine, Hanyang University, Seoul</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Borg, Ke" sort="Borg, Ke" uniqKey="Borg " first=" Ke" last="Borg"> Ke Borg</name><affiliation wicri:level="1"><nlm:affiliation>Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></affiliation></author><author><name sortKey="Birney, Ewan" sort="Birney, Ewan" uniqKey="Birney E" first="Ewan" last="Birney">Ewan Birney</name><affiliation wicri:level="1"><nlm:affiliation>European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Stunnenberg, Hendrik G" sort="Stunnenberg, Hendrik G" uniqKey="Stunnenberg H" first="Hendrik G" last="Stunnenberg">Hendrik G. Stunnenberg</name><affiliation wicri:level="3"><nlm:affiliation>Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen, the Netherlands.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Van De Vijver, Marc J" sort="Van De Vijver, Marc J" uniqKey="Van De Vijver M" first="Marc J" last="Van De Vijver">Marc J. Van De Vijver</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Pathology, Academic Medical Center, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></affiliation></author><author><name sortKey="B Rresen Dale, Anne Lise" sort="B Rresen Dale, Anne Lise" uniqKey="B Rresen Dale A" first="Anne-Lise" last="B Rresen-Dale">Anne-Lise B Rresen-Dale</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</region></placeName></affiliation></author><author><name sortKey="Martens, John W M" sort="Martens, John W M" uniqKey="Martens J" first="John W M" last="Martens">John W M. Martens</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics, Erasmus University Medical Center, Rotterdam, the Netherlands.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics, Erasmus University Medical Center, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Span, Paul N" sort="Span, Paul N" uniqKey="Span P" first="Paul N" last="Span">Paul N. Span</name><affiliation wicri:level="3"><nlm:affiliation>Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Radiation Oncology, Radboud University Medical Center, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R" last="Lakhani">Sunil R. Lakhani</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Clinical Research and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Clinical Research and School of Medicine, The University of Queensland, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Vincent Salomon, Anne" sort="Vincent Salomon, Anne" uniqKey="Vincent Salomon A" first="Anne" last="Vincent-Salomon">Anne Vincent-Salomon</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Institut Curie, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Pathology, Institut Curie, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Sotiriou, Christos" sort="Sotiriou, Christos" uniqKey="Sotiriou C" first="Christos" last="Sotiriou">Christos Sotiriou</name><affiliation wicri:level="4"><nlm:affiliation>Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region><settlement type="city">Bruxelles</settlement></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation></author><author><name sortKey="Tutt, Andrew" sort="Tutt, Andrew" uniqKey="Tutt A" first="Andrew" last="Tutt">Andrew Tutt</name><affiliation wicri:level="3"><nlm:affiliation>Breast Cancer Now Research Unit, King's College, London, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Breast Cancer Now Research Unit, King's College, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Thompson, Alastair M" sort="Thompson, Alastair M" uniqKey="Thompson A" first="Alastair M" last="Thompson">Alastair M. Thompson</name><affiliation wicri:level="2"><nlm:affiliation>Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Van Laere, Steven" sort="Van Laere, Steven" uniqKey="Van Laere S" first="Steven" last="Van Laere">Steven Van Laere</name><affiliation wicri:level="4"><nlm:affiliation>Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region>Région flamande</region><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation></author><author><name sortKey="Richardson, Andrea L" sort="Richardson, Andrea L" uniqKey="Richardson A" first="Andrea L" last="Richardson">Andrea L. Richardson</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Viari, Alain" sort="Viari, Alain" uniqKey="Viari A" first="Alain" last="Viari">Alain Viari</name><affiliation wicri:level="1"><nlm:affiliation>Equipe Erable, INRIA Grenoble-Rhône-Alpes, Montbonnot-Saint Martin, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Equipe Erable, INRIA Grenoble-Rhône-Alpes, Montbonnot-Saint Martin</wicri:regionArea><wicri:noRegion>Montbonnot-Saint Martin</wicri:noRegion><wicri:noRegion>Montbonnot-Saint Martin</wicri:noRegion></affiliation></author><author><name sortKey="Campbell, Peter J" sort="Campbell, Peter J" uniqKey="Campbell P" first="Peter J" last="Campbell">Peter J. Campbell</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R" last="Stratton">Michael R. Stratton</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author><author><name sortKey="Nik Zainal, Serena" sort="Nik Zainal, Serena" uniqKey="Nik Zainal S" first="Serena" last="Nik-Zainal">Serena Nik-Zainal</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Hinxton, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Hinxton</wicri:regionArea><wicri:noRegion>Hinxton</wicri:noRegion></affiliation></author></analytic><series><title level="j">Nature medicine</title><idno type="eISSN">1546-170X</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Area Under Curve</term><term>BRCA1 Protein (deficiency)</term><term>BRCA1 Protein (genetics)</term><term>BRCA2 Protein (deficiency)</term><term>BRCA2 Protein (genetics)</term><term>Breast Neoplasms (drug therapy)</term><term>Breast Neoplasms (genetics)</term><term>Breast Neoplasms, Male (genetics)</term><term>DNA Mutational Analysis</term><term>Female</term><term>Humans</term><term>Logistic Models</term><term>Male</term><term>Models, Genetic</term><term>Mutation</term><term>Ovarian Neoplasms (drug therapy)</term><term>Ovarian Neoplasms (genetics)</term><term>Pancreatic Neoplasms (drug therapy)</term><term>Pancreatic Neoplasms (genetics)</term><term>Poly(ADP-ribose) Polymerase Inhibitors (therapeutic use)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Aire sous la courbe</term><term>Analyse de mutations d'ADN</term><term>Femelle</term><term>Humains</term><term>Inhibiteurs de poly(ADP-ribose) polymérases (usage thérapeutique)</term><term>Modèles génétiques</term><term>Modèles logistiques</term><term>Mutation</term><term>Mâle</term><term>Protéine BRCA1 (déficit)</term><term>Protéine BRCA1 (génétique)</term><term>Protéine BRCA2 (déficit)</term><term>Protéine BRCA2 (génétique)</term><term>Tumeur du sein de l'homme (génétique)</term><term>Tumeurs de l'ovaire (génétique)</term><term>Tumeurs de l'ovaire (traitement médicamenteux)</term><term>Tumeurs du pancréas (génétique)</term><term>Tumeurs du pancréas (traitement médicamenteux)</term><term>Tumeurs du sein (génétique)</term><term>Tumeurs du sein (traitement médicamenteux)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>BRCA1 Protein</term><term>BRCA2 Protein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>BRCA1 Protein</term><term>BRCA2 Protein</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Breast Neoplasms</term><term>Ovarian Neoplasms</term><term>Pancreatic Neoplasms</term></keywords><keywords scheme="MESH" qualifier="déficit" xml:lang="fr"><term>Protéine BRCA1</term><term>Protéine BRCA2</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Breast Neoplasms</term><term>Breast Neoplasms, Male</term><term>Ovarian Neoplasms</term><term>Pancreatic Neoplasms</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéine BRCA1</term><term>Protéine BRCA2</term><term>Tumeur du sein de l'homme</term><term>Tumeurs de l'ovaire</term><term>Tumeurs du pancréas</term><term>Tumeurs du sein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Poly(ADP-ribose) Polymerase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Tumeurs de l'ovaire</term><term>Tumeurs du pancréas</term><term>Tumeurs du sein</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Inhibiteurs de poly(ADP-ribose) polymérases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Area Under Curve</term><term>DNA Mutational Analysis</term><term>Female</term><term>Humans</term><term>Logistic Models</term><term>Male</term><term>Models, Genetic</term><term>Mutation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Aire sous la courbe</term><term>Analyse de mutations d'ADN</term><term>Femelle</term><term>Humains</term><term>Modèles génétiques</term><term>Modèles logistiques</term><term>Mutation</term><term>Mâle</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Australie</li><li>Belgique</li><li>Corée du Sud</li><li>France</li><li>Islande</li><li>Norvège</li><li>Pays-Bas</li><li>Royaume-Uni</li><li>Suède</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Auvergne-Rhône-Alpes</li><li>Grand Londres</li><li>Gueldre</li><li>Hollande-Méridionale</li><li>Hollande-Septentrionale</li><li>Massachusetts</li><li>Province d'Anvers</li><li>Rhône-Alpes</li><li>Région capitale de Séoul</li><li>Région de Bruxelles-Capitale</li><li>Région flamande</li><li>Texas</li><li>État de New York</li><li>Île-de-France</li><li>Østlandet</li></region><settlement><li>Amsterdam</li><li>Anvers</li><li>Bruxelles</li><li>Londres</li><li>Lyon</li><li>Nimègue</li><li>Oslo</li><li>Paris</li><li>Rotterdam</li><li>Séoul</li></settlement><orgName><li>Université d'Anvers</li><li>Université libre de Bruxelles</li></orgName></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Davies, Helen" sort="Davies, Helen" uniqKey="Davies H" first="Helen" last="Davies">Helen Davies</name></noRegion><name sortKey="Birney, Ewan" sort="Birney, Ewan" uniqKey="Birney E" first="Ewan" last="Birney">Ewan Birney</name><name sortKey="Campbell, Peter J" sort="Campbell, Peter J" uniqKey="Campbell P" first="Peter J" last="Campbell">Peter J. Campbell</name><name sortKey="Glodzik, Dominik" sort="Glodzik, Dominik" uniqKey="Glodzik D" first="Dominik" last="Glodzik">Dominik Glodzik</name><name sortKey="Martin, Sancha" sort="Martin, Sancha" uniqKey="Martin S" first="Sancha" last="Martin">Sancha Martin</name><name sortKey="Morganella, Sandro" sort="Morganella, Sandro" uniqKey="Morganella S" first="Sandro" last="Morganella">Sandro Morganella</name><name sortKey="Nik Zainal, Serena" sort="Nik Zainal, Serena" uniqKey="Nik Zainal S" first="Serena" last="Nik-Zainal">Serena Nik-Zainal</name><name sortKey="Raine, Keiran" sort="Raine, Keiran" uniqKey="Raine K" first="Keiran" last="Raine">Keiran Raine</name><name sortKey="Ramakrishna, Manasa" sort="Ramakrishna, Manasa" uniqKey="Ramakrishna M" first="Manasa" last="Ramakrishna">Manasa Ramakrishna</name><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R" last="Stratton">Michael R. Stratton</name><name sortKey="Tutt, Andrew" sort="Tutt, Andrew" uniqKey="Tutt A" first="Andrew" last="Tutt">Andrew Tutt</name><name sortKey="Yates, Lucy R" sort="Yates, Lucy R" uniqKey="Yates L" first="Lucy R" last="Yates">Lucy R. Yates</name><name sortKey="Zou, Xueqing" sort="Zou, Xueqing" uniqKey="Zou X" first="Xueqing" last="Zou">Xueqing Zou</name></country><country name="Suède"><noRegion><name sortKey="Staaf, Johan" sort="Staaf, Johan" uniqKey="Staaf J" first="Johan" last="Staaf">Johan Staaf</name></noRegion><name sortKey="Borg, Ke" sort="Borg, Ke" uniqKey="Borg " first=" Ke" last="Borg"> Ke Borg</name></country><country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Boyault, Sandrine" sort="Boyault, Sandrine" uniqKey="Boyault S" first="Sandrine" last="Boyault">Sandrine Boyault</name></region><name sortKey="Viari, Alain" sort="Viari, Alain" uniqKey="Viari A" first="Alain" last="Viari">Alain Viari</name><name sortKey="Vincent Salomon, Anne" sort="Vincent Salomon, Anne" uniqKey="Vincent Salomon A" first="Anne" last="Vincent-Salomon">Anne Vincent-Salomon</name></country><country name="Pays-Bas"><region name="Hollande-Méridionale"><name sortKey="Sieuwerts, Anieta M" sort="Sieuwerts, Anieta M" uniqKey="Sieuwerts A" first="Anieta M" last="Sieuwerts">Anieta M. Sieuwerts</name></region><name sortKey="Martens, John W M" sort="Martens, John W M" uniqKey="Martens J" first="John W M" last="Martens">John W M. Martens</name><name sortKey="Span, Paul N" sort="Span, Paul N" uniqKey="Span P" first="Paul N" last="Span">Paul N. Span</name><name sortKey="Stunnenberg, Hendrik G" sort="Stunnenberg, Hendrik G" uniqKey="Stunnenberg H" first="Hendrik G" last="Stunnenberg">Hendrik G. Stunnenberg</name><name sortKey="Van De Vijver, Marc J" sort="Van De Vijver, Marc J" uniqKey="Van De Vijver M" first="Marc J" last="Van De Vijver">Marc J. Van De Vijver</name></country><country name="Australie"><noRegion><name sortKey="Simpson, Peter T" sort="Simpson, Peter T" uniqKey="Simpson P" first="Peter T" last="Simpson">Peter T. Simpson</name></noRegion><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R" last="Lakhani">Sunil R. Lakhani</name></country><country name="États-Unis"><region name="État de New York"><name sortKey="King, Tari A" sort="King, Tari A" uniqKey="King T" first="Tari A" last="King">Tari A. King</name></region><name sortKey="Richardson, Andrea L" sort="Richardson, Andrea L" uniqKey="Richardson A" first="Andrea L" last="Richardson">Andrea L. Richardson</name><name sortKey="Thompson, Alastair M" sort="Thompson, Alastair M" uniqKey="Thompson A" first="Alastair M" last="Thompson">Alastair M. Thompson</name></country><country name="Islande"><noRegion><name sortKey="Eyfjord, Jorunn E" sort="Eyfjord, Jorunn E" uniqKey="Eyfjord J" first="Jorunn E" last="Eyfjord">Jorunn E. Eyfjord</name></noRegion></country><country name="Corée du Sud"><region name="Région capitale de Séoul"><name sortKey="Kong, Gu" sort="Kong, Gu" uniqKey="Kong G" first="Gu" last="Kong">Gu Kong</name></region></country><country name="Norvège"><region name="Østlandet"><name sortKey="B Rresen Dale, Anne Lise" sort="B Rresen Dale, Anne Lise" uniqKey="B Rresen Dale A" first="Anne-Lise" last="B Rresen-Dale">Anne-Lise B Rresen-Dale</name></region></country><country name="Belgique"><region name="Région de Bruxelles-Capitale"><name sortKey="Sotiriou, Christos" sort="Sotiriou, Christos" uniqKey="Sotiriou C" first="Christos" last="Sotiriou">Christos Sotiriou</name></region><name sortKey="Van Laere, Steven" sort="Van Laere, Steven" uniqKey="Van Laere S" first="Steven" last="Van Laere">Steven Van Laere</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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