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dc.contributor.authorStaaf, Johanen
dc.contributor.authorGlodzik, Dominiken
dc.contributor.authorBosch, Anaen
dc.contributor.authorVallon-Christersson, Johanen
dc.contributor.authorReuterswärd, Christelen
dc.contributor.authorHäkkinen, Jarien
dc.contributor.authorDegasperi, Andreaen
dc.contributor.authorAmarante, Tauanne Diasen
dc.contributor.authorSaal, Lao Hen
dc.contributor.authorHegardt, Ceciliaen
dc.contributor.authorStobart, Hilaryen
dc.contributor.authorEhinger, Annaen
dc.contributor.authorLarsson, Christeren
dc.contributor.authorRydén, Lisaen
dc.contributor.authorLoman, Niklasen
dc.contributor.authorMalmberg, Martinen
dc.contributor.authorKvist, Andersen
dc.contributor.authorEhrencrona, Hansen
dc.contributor.authorDavies, Helenen
dc.contributor.authorBorg, Åkeen
dc.contributor.authorNik-Zainal Abidin, Serenaen
dc.date.accessioned2019-09-10T12:48:09Z
dc.date.available2019-09-10T12:48:09Z
dc.date.issued2019-10en
dc.identifier.issn1078-8956
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/296705
dc.description.abstractWhole genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore clinical value of WGS, we sequenced 254 triple negative breast cancers (TNBC) with associated treatment and outcome data collected between 2010-2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have Homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (Hazard Ratio, HR=0.42, 95% confidence interval, CI=0.2-0.87), and distant relapse-free interval (HR=0.31, CI=0.13-0.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient - another targetable defect, not typically sought; and was enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherSpringer Nature
dc.subjectHumansen
dc.subjectNeoplasm Recurrence, Localen
dc.subjectPrognosisen
dc.subjectDisease-Free Survivalen
dc.subjectGenetics, Populationen
dc.subjectDNA Methylationen
dc.subjectGerm-Line Mutationen
dc.subjectAdulten
dc.subjectAgeden
dc.subjectAged, 80 and overen
dc.subjectMiddle Ageden
dc.subjectFemaleen
dc.subjectPromoter Regions, Geneticen
dc.subjectTriple Negative Breast Neoplasmsen
dc.subjectWhole Genome Sequencingen
dc.titleWhole-genome sequencing of triple-negative breast cancers in a population-based clinical study.en
dc.typeArticle
prism.endingPage1533
prism.issueIdentifier10en
prism.publicationDate2019en
prism.publicationNameNature medicineen
prism.startingPage1526
prism.volume25en
dc.identifier.doi10.17863/CAM.43747
dcterms.dateAccepted2019-08-15en
rioxxterms.versionofrecord10.1038/s41591-019-0582-4en
rioxxterms.versionAM*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-10en
dc.contributor.orcidStaaf, Johan [0000-0001-5254-5115]
dc.contributor.orcidGlodzik, Dominik [0000-0001-8112-9073]
dc.contributor.orcidVallon-Christersson, Johan [0000-0002-2195-0385]
dc.contributor.orcidHäkkinen, Jari [0000-0002-8466-9179]
dc.contributor.orcidDegasperi, Andrea [0000-0001-6879-0596]
dc.contributor.orcidAmarante, Tauanne Dias [0000-0002-1999-9753]
dc.contributor.orcidSaal, Lao H [0000-0002-0815-1896]
dc.contributor.orcidEhinger, Anna [0000-0001-9225-7396]
dc.contributor.orcidEhrencrona, Hans [0000-0002-5589-3622]
dc.contributor.orcidNik-Zainal Abidin, Serena [0000-0001-5054-1727]
dc.identifier.eissn1546-170X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (23916)
pubs.funder-project-idCancer Research UK (25274)
pubs.funder-project-idCancer Research UK (23433)
cam.orpheus.successThu Jan 30 10:39:28 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2020-04-30


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