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dc.contributor.authorGlodzik, Den
dc.contributor.authorMorganella, Sen
dc.contributor.authorDavies, Helenen
dc.contributor.authorSimpson, PTen
dc.contributor.authorLi, Yen
dc.contributor.authorZou, Xueqingen
dc.contributor.authorDiez-Perez, Jen
dc.contributor.authorStaaf, Jen
dc.contributor.authorAlexandrov, LBen
dc.contributor.authorSmid, Men
dc.contributor.authorBrinkman, ABen
dc.contributor.authorRye, IHen
dc.contributor.authorRussnes, Hen
dc.contributor.authorRaine, Ken
dc.contributor.authorPurdie, CAen
dc.contributor.authorLakhani, SRen
dc.contributor.authorThompson, AMen
dc.contributor.authorBirney, Een
dc.contributor.authorStunnenberg, HGen
dc.contributor.authorvan de Vijver, MJen
dc.contributor.authorMartens, JWMen
dc.contributor.authorBørresen-Dale, A-Len
dc.contributor.authorRichardson, ALen
dc.contributor.authorKong, Gen
dc.contributor.authorViari, Aen
dc.contributor.authorEaston, Douglasen
dc.contributor.authorEvan, Gerarden
dc.contributor.authorCampbell, PJen
dc.contributor.authorStratton, MRen
dc.contributor.authorNik-Zainal Abidin, Serenaen
dc.date.accessioned2017-03-10T10:10:07Z
dc.date.available2017-03-10T10:10:07Z
dc.date.issued2017-03-01en
dc.identifier.issn1061-4036
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/262998
dc.description.abstractSomatic 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.
dc.description.sponsorshipDG is supported by the EU-FP7-SUPPRESSTEM project. SN-Z is funded by a Wellcome Trust Intermediate Fellowship (WT100183MA) and is a Wellcome Beit Fellow. For more information, please visit the publisher's website.
dc.languageengen
dc.language.isoenen
dc.publisherNature Publishing Group
dc.subjectbreast canceren
dc.subjectgenetics researchen
dc.subjectgenomicsen
dc.titleA somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancersen
dc.typeArticle
prism.endingPage348
prism.issueIdentifier3en
prism.publicationDate2017en
prism.publicationNameNature Geneticsen
prism.startingPage341
prism.volume49en
dc.identifier.doi10.17863/CAM.8300
dcterms.dateAccepted2016-12-16en
rioxxterms.versionofrecord10.1038/ng.3771en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-03-01en
dc.contributor.orcidZou, Xueqing [0000-0003-1143-1028]
dc.contributor.orcidEaston, Douglas [0000-0003-2444-3247]
dc.contributor.orcidEvan, Gerard [0000-0003-0412-1216]
dc.contributor.orcidNik-Zainal Abidin, Serena [0000-0001-5054-1727]
dc.identifier.eissn1546-1718
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (19013)
pubs.funder-project-idEC FP7 CP (242006)
cam.issuedOnline2017-01-23en
rioxxterms.freetoread.startdate2017-07-23


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