A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers.
Identifieur interne : 001281 ( PubMed/Checkpoint ); précédent : 001280; suivant : 001282A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers.
Auteurs : Dominik Glodzik [Royaume-Uni] ; Sandro Morganella [Royaume-Uni] ; Helen Davies [Royaume-Uni] ; Peter T. Simpson [Australie] ; Yilong Li [Royaume-Uni] ; Xueqing Zou [Royaume-Uni] ; Javier Diez-Perez [Royaume-Uni] ; Johan Staaf [Suède] ; Ludmil B. Alexandrov [Royaume-Uni] ; Marcel Smid [Pays-Bas] ; Arie B. Brinkman [Pays-Bas] ; Inga Hansine Rye [Norvège] ; Hege Russnes [Norvège] ; Keiran Raine [Royaume-Uni] ; Colin A. Purdie [Royaume-Uni] ; Sunil R. Lakhani [Australie] ; Alastair M. Thompson [Royaume-Uni] ; Ewan Birney [Royaume-Uni] ; Hendrik G. Stunnenberg [Pays-Bas] ; Marc J. Van De Vijver [Pays-Bas] ; John W M. Martens [Pays-Bas] ; Anne-Lise B Rresen-Dale [Norvège] ; Andrea L. Richardson [États-Unis] ; Gu Kong [Corée du Sud] ; Alain Viari [France] ; Douglas Easton [Royaume-Uni] ; Gerard Evan [Royaume-Uni] ; Peter J. Campbell [Royaume-Uni] ; Michael R. Stratton [Royaume-Uni] ; Serena Nik-Zainal [Royaume-Uni]Source :
- Nature genetics [ 1546-1718 ] ; 2017.
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Abstract
Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.
DOI: 10.1038/ng.3771
PubMed: 28112740
Affiliations:
- Australie, Corée du Sud, France, Norvège, Pays-Bas, Royaume-Uni, Suède, États-Unis
- Angleterre, Angleterre de l'Est, Gueldre, Hollande-Méridionale, Hollande-Septentrionale, Massachusetts, Région capitale de Séoul, Østlandet
- Amsterdam, Cambridge, Nimègue, Oslo, Rotterdam, Séoul
- Université de Cambridge
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Brinkman</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="Rye, Inga Hansine" sort="Rye, Inga Hansine" uniqKey="Rye I" first="Inga Hansine" last="Rye">Inga Hansine Rye</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</region></placeName></affiliation></author><author><name sortKey="Russnes, Hege" sort="Russnes, Hege" uniqKey="Russnes H" first="Hege" last="Russnes">Hege Russnes</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</wicri:noRegion></affiliation></author><author><name sortKey="Purdie, Colin A" sort="Purdie, Colin A" uniqKey="Purdie C" first="Colin A" last="Purdie">Colin A. Purdie</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Ninewells Hospital &Medical School, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pathology, Ninewells Hospital &Medical School, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></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>The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></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="1"><nlm:affiliation>Department of Pathology, Ninewells Hospital &Medical School, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pathology, Ninewells Hospital &Medical School, Dundee</wicri:regionArea><wicri:noRegion>Dundee</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, Cambridgeshire, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridgeshire</wicri:regionArea><wicri:noRegion>Cambridgeshire</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 Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, 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 Netherlands, 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="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="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 Netherlands, 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 Netherlands, 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="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, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</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="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, South 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="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="Easton, Douglas" sort="Easton, Douglas" uniqKey="Easton D" first="Douglas" last="Easton">Douglas Easton</name><affiliation wicri:level="4"><nlm:affiliation>Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Evan, Gerard" sort="Evan, Gerard" uniqKey="Evan G" first="Gerard" last="Evan">Gerard Evan</name><affiliation wicri:level="4"><nlm:affiliation>Department of Biochemistry, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Biochemistry, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28112740</idno><idno type="pmid">28112740</idno><idno type="doi">10.1038/ng.3771</idno><idno type="wicri:Area/PubMed/Corpus">000F55</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000F55</idno><idno type="wicri:Area/PubMed/Curation">000F52</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000F52</idno><idno type="wicri:Area/PubMed/Checkpoint">000F52</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000F52</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers.</title><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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</wicri:noRegion></affiliation></author><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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</wicri:noRegion></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>The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></affiliation></author><author><name sortKey="Li, Yilong" sort="Li, Yilong" uniqKey="Li Y" first="Yilong" last="Li">Yilong Li</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</wicri:noRegion></affiliation></author><author><name sortKey="Diez Perez, Javier" sort="Diez Perez, Javier" uniqKey="Diez Perez J" first="Javier" last="Diez-Perez">Javier Diez-Perez</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</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>Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></affiliation></author><author><name sortKey="Alexandrov, Ludmil B" sort="Alexandrov, Ludmil B" uniqKey="Alexandrov L" first="Ludmil B" last="Alexandrov">Ludmil B. Alexandrov</name><affiliation wicri:level="1"><nlm:affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</wicri:noRegion></affiliation></author><author><name sortKey="Smid, Marcel" sort="Smid, Marcel" uniqKey="Smid M" first="Marcel" last="Smid">Marcel Smid</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, 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 Netherlands, 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="Brinkman, Arie B" sort="Brinkman, Arie B" uniqKey="Brinkman A" first="Arie B" last="Brinkman">Arie B. Brinkman</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="Rye, Inga Hansine" sort="Rye, Inga Hansine" uniqKey="Rye I" first="Inga Hansine" last="Rye">Inga Hansine Rye</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</region></placeName></affiliation></author><author><name sortKey="Russnes, Hege" sort="Russnes, Hege" uniqKey="Russnes H" first="Hege" last="Russnes">Hege Russnes</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</wicri:noRegion></affiliation></author><author><name sortKey="Purdie, Colin A" sort="Purdie, Colin A" uniqKey="Purdie C" first="Colin A" last="Purdie">Colin A. Purdie</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Ninewells Hospital &Medical School, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pathology, Ninewells Hospital &Medical School, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></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>The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland</wicri:regionArea><wicri:noRegion>Queensland</wicri:noRegion></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="1"><nlm:affiliation>Department of Pathology, Ninewells Hospital &Medical School, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pathology, Ninewells Hospital &Medical School, Dundee</wicri:regionArea><wicri:noRegion>Dundee</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, Cambridgeshire, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridgeshire</wicri:regionArea><wicri:noRegion>Cambridgeshire</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 Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, 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 Netherlands, 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="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="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 Netherlands, 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 Netherlands, 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="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, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</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="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, South 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="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="Easton, Douglas" sort="Easton, Douglas" uniqKey="Easton D" first="Douglas" last="Easton">Douglas Easton</name><affiliation wicri:level="4"><nlm:affiliation>Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Evan, Gerard" sort="Evan, Gerard" uniqKey="Evan G" first="Gerard" last="Evan">Gerard Evan</name><affiliation wicri:level="4"><nlm:affiliation>Department of Biochemistry, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Biochemistry, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</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, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Wellcome Trust Sanger Institute, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</wicri:noRegion></affiliation></author></analytic><series><title level="j">Nature genetics</title><idno type="eISSN">1546-1718</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Breast Neoplasms (genetics)</term><term>DNA Breaks, Double-Stranded</term><term>DNA Repair (genetics)</term><term>Female</term><term>Gene Expression (genetics)</term><term>Genetic Loci (genetics)</term><term>Genome (genetics)</term><term>Humans</term><term>Mutation (genetics)</term><term>Regulatory Sequences, Nucleic Acid (genetics)</term><term>Transcriptome (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Cassures double-brin de l'ADN</term><term>Expression des gènes (génétique)</term><term>Femelle</term><term>Génome (génétique)</term><term>Humains</term><term>Locus génétiques (génétique)</term><term>Mutation (génétique)</term><term>Réparation de l'ADN (génétique)</term><term>Séquences d'acides nucléiques régulatrices (génétique)</term><term>Transcriptome (génétique)</term><term>Tumeurs du sein (génétique)</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Breast Neoplasms</term><term>DNA Repair</term><term>Gene Expression</term><term>Genetic Loci</term><term>Genome</term><term>Mutation</term><term>Regulatory Sequences, Nucleic Acid</term><term>Transcriptome</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Expression des gènes</term><term>Génome</term><term>Locus génétiques</term><term>Mutation</term><term>Réparation de l'ADN</term><term>Séquences d'acides nucléiques régulatrices</term><term>Transcriptome</term><term>Tumeurs du sein</term></keywords><keywords scheme="MESH" xml:lang="en"><term>DNA Breaks, Double-Stranded</term><term>Female</term><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cassures double-brin de l'ADN</term><term>Femelle</term><term>Humains</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28112740</PMID><DateCreated><Year>2017</Year><Month>01</Month><Day>23</Day></DateCreated><DateCompleted><Year>2017</Year><Month>09</Month><Day>05</Day></DateCompleted><DateRevised><Year>2017</Year><Month>10</Month><Day>27</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1546-1718</ISSN><JournalIssue CitedMedium="Internet"><Volume>49</Volume><Issue>3</Issue><PubDate><Year>2017</Year><Month>Mar</Month></PubDate></JournalIssue><Title>Nature genetics</Title><ISOAbbreviation>Nat. Genet.</ISOAbbreviation></Journal><ArticleTitle>A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers.</ArticleTitle><Pagination><MedlinePgn>341-348</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1038/ng.3771</ELocationID><Abstract><AbstractText>Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Glodzik</LastName><ForeName>Dominik</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Morganella</LastName><ForeName>Sandro</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Davies</LastName><ForeName>Helen</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Simpson</LastName><ForeName>Peter T</ForeName><Initials>PT</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-4816-8289</Identifier><AffiliationInfo><Affiliation>The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Yilong</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zou</LastName><ForeName>Xueqing</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Diez-Perez</LastName><ForeName>Javier</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Staaf</LastName><ForeName>Johan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Alexandrov</LastName><ForeName>Ludmil B</ForeName><Initials>LB</Initials><AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Smid</LastName><ForeName>Marcel</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, the Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brinkman</LastName><ForeName>Arie B</ForeName><Initials>AB</Initials><AffiliationInfo><Affiliation>Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen, the Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rye</LastName><ForeName>Inga Hansine</ForeName><Initials>IH</Initials><AffiliationInfo><Affiliation>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Russnes</LastName><ForeName>Hege</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Raine</LastName><ForeName>Keiran</ForeName><Initials>K</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-5634-1539</Identifier><AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Purdie</LastName><ForeName>Colin A</ForeName><Initials>CA</Initials><AffiliationInfo><Affiliation>Department of Pathology, Ninewells Hospital &Medical School, Dundee, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lakhani</LastName><ForeName>Sunil R</ForeName><Initials>SR</Initials><Identifier Source="ORCID">http://orcid.org/0000-0003-1879-2555</Identifier><AffiliationInfo><Affiliation>The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland, Australia.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Thompson</LastName><ForeName>Alastair M</ForeName><Initials>AM</Initials><AffiliationInfo><Affiliation>Department of Pathology, Ninewells Hospital &Medical School, Dundee, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Birney</LastName><ForeName>Ewan</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridgeshire, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stunnenberg</LastName><ForeName>Hendrik G</ForeName><Initials>HG</Initials><AffiliationInfo><Affiliation>Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, the Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van de Vijver</LastName><ForeName>Marc J</ForeName><Initials>MJ</Initials><AffiliationInfo><Affiliation>Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martens</LastName><ForeName>John W M</ForeName><Initials>JW</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-3428-3366</Identifier><AffiliationInfo><Affiliation>Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, the Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Børresen-Dale</LastName><ForeName>Anne-Lise</ForeName><Initials>AL</Initials><AffiliationInfo><Affiliation>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Richardson</LastName><ForeName>Andrea L</ForeName><Initials>AL</Initials><AffiliationInfo><Affiliation>Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Dana-Farber Cancer Institute, Boston, Massachusetts, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kong</LastName><ForeName>Gu</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Viari</LastName><ForeName>Alain</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Equipe Erable, INRIA Grenoble-Rhône-Alpes, Montbonnot-Saint Martin, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Synergie Lyon Cancer, Centre Léon Bérard, Lyon, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Easton</LastName><ForeName>Douglas</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Evan</LastName><ForeName>Gerard</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, University of Cambridge, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Campbell</LastName><ForeName>Peter J</ForeName><Initials>PJ</Initials><AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stratton</LastName><ForeName>Michael R</ForeName><Initials>MR</Initials><AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nik-Zainal</LastName><ForeName>Serena</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Wellcome Trust Sanger Institute, Cambridge, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>01</Month><Day>23</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Nat 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Repair</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015870" MajorTopicYN="N">Gene Expression</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D056426" MajorTopicYN="N">Genetic Loci</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016678" MajorTopicYN="N">Genome</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="N">Mutation</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012045" MajorTopicYN="N">Regulatory Sequences, Nucleic Acid</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059467" MajorTopicYN="N">Transcriptome</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>04</Month><Day>19</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>12</Month><Day>16</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>1</Month><Day>24</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>9</Month><Day>7</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>1</Month><Day>24</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28112740</ArticleId><ArticleId IdType="pii">ng.3771</ArticleId><ArticleId IdType="doi">10.1038/ng.3771</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Australie</li><li>Corée du Sud</li><li>France</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>Angleterre de l'Est</li><li>Gueldre</li><li>Hollande-Méridionale</li><li>Hollande-Septentrionale</li><li>Massachusetts</li><li>Région capitale de Séoul</li><li>Østlandet</li></region><settlement><li>Amsterdam</li><li>Cambridge</li><li>Nimègue</li><li>Oslo</li><li>Rotterdam</li><li>Séoul</li></settlement><orgName><li>Université de Cambridge</li></orgName></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Glodzik, Dominik" sort="Glodzik, Dominik" uniqKey="Glodzik D" first="Dominik" last="Glodzik">Dominik Glodzik</name></noRegion><name sortKey="Alexandrov, Ludmil B" sort="Alexandrov, Ludmil B" uniqKey="Alexandrov L" first="Ludmil B" last="Alexandrov">Ludmil B. Alexandrov</name><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="Davies, Helen" sort="Davies, Helen" uniqKey="Davies H" first="Helen" last="Davies">Helen Davies</name><name sortKey="Diez Perez, Javier" sort="Diez Perez, Javier" uniqKey="Diez Perez J" first="Javier" last="Diez-Perez">Javier Diez-Perez</name><name sortKey="Easton, Douglas" sort="Easton, Douglas" uniqKey="Easton D" first="Douglas" last="Easton">Douglas Easton</name><name sortKey="Evan, Gerard" sort="Evan, Gerard" uniqKey="Evan G" first="Gerard" last="Evan">Gerard Evan</name><name sortKey="Li, Yilong" sort="Li, Yilong" uniqKey="Li Y" first="Yilong" last="Li">Yilong Li</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="Purdie, Colin A" sort="Purdie, Colin A" uniqKey="Purdie C" first="Colin A" last="Purdie">Colin A. Purdie</name><name sortKey="Raine, Keiran" sort="Raine, Keiran" uniqKey="Raine K" first="Keiran" last="Raine">Keiran Raine</name><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R" last="Stratton">Michael R. Stratton</name><name sortKey="Thompson, Alastair M" sort="Thompson, Alastair M" uniqKey="Thompson A" first="Alastair M" last="Thompson">Alastair M. Thompson</name><name sortKey="Zou, Xueqing" sort="Zou, Xueqing" uniqKey="Zou X" first="Xueqing" last="Zou">Xueqing Zou</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="Suède"><noRegion><name sortKey="Staaf, Johan" sort="Staaf, Johan" uniqKey="Staaf J" first="Johan" last="Staaf">Johan Staaf</name></noRegion></country><country name="Pays-Bas"><region name="Hollande-Méridionale"><name sortKey="Smid, Marcel" sort="Smid, Marcel" uniqKey="Smid M" first="Marcel" last="Smid">Marcel Smid</name></region><name sortKey="Brinkman, Arie B" sort="Brinkman, Arie B" uniqKey="Brinkman A" first="Arie B" last="Brinkman">Arie B. Brinkman</name><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="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="Norvège"><region name="Østlandet"><name sortKey="Rye, Inga Hansine" sort="Rye, Inga Hansine" uniqKey="Rye I" first="Inga Hansine" last="Rye">Inga Hansine Rye</name></region><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><name sortKey="Russnes, Hege" sort="Russnes, Hege" uniqKey="Russnes H" first="Hege" last="Russnes">Hege Russnes</name></country><country name="États-Unis"><region name="Massachusetts"><name sortKey="Richardson, Andrea L" sort="Richardson, Andrea L" uniqKey="Richardson A" first="Andrea L" last="Richardson">Andrea L. Richardson</name></region></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="France"><noRegion><name sortKey="Viari, Alain" sort="Viari, Alain" uniqKey="Viari A" first="Alain" last="Viari">Alain Viari</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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