Show simple item record

dc.contributor.authorGundem, Gen
dc.contributor.authorVan Loo, Pen
dc.contributor.authorKremeyer, Ben
dc.contributor.authorAlexandrov, LBen
dc.contributor.authorTubio, JMCen
dc.contributor.authorPapaemmanuil, Een
dc.contributor.authorBrewer, DSen
dc.contributor.authorKallio, HMLen
dc.contributor.authorHögnäs, Gen
dc.contributor.authorAnnala, Men
dc.contributor.authorKivinummi, Ken
dc.contributor.authorGoody, Ven
dc.contributor.authorLatimer, Cen
dc.contributor.authorO'Meara, Sen
dc.contributor.authorDawson, KJen
dc.contributor.authorIsaacs, Wen
dc.contributor.authorEmmert-Buck, MRen
dc.contributor.authorNykter, Men
dc.contributor.authorFoster, Cen
dc.contributor.authorKote-Jarai, Zen
dc.contributor.authorEaston, Douglasen
dc.contributor.authorWhitaker, HCen
dc.contributor.authorICGC Prostate Group,en
dc.contributor.authorNeal, DEen
dc.contributor.authorCooper, CSen
dc.contributor.authorEeles, RAen
dc.contributor.authorVisakorpi, Ten
dc.contributor.authorCampbell, PJen
dc.contributor.authorMcDermott, Uen
dc.contributor.authorWedge, DCen
dc.contributor.authorBova, GSen
dc.date.accessioned2017-09-12T12:50:24Z
dc.date.available2017-09-12T12:50:24Z
dc.date.issued2015-04-16en
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/267182
dc.description.abstractCancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.
dc.description.sponsorshipThis is an ICGC Prostate Cancer study funded by: Cancer Research UK (2011-present); NIH NCI Intramural Program (2013-2014); Academy of Finland (2011-present); Cancer Society of Finland (2013-present); PELICAN Autopsy Study family members and friends (1998-2004); John and Kathe Dyson (2000); US National Cancer Institute CA92234 (2000-2005); American Cancer Society (1998-2000); Johns Hopkins University Department of Pathology (1997-2011); Women's Board of Johns Hopkins Hospital (1998); The Grove Foundation (1998); Association for the Cure of Cancer of the Prostate (1994-1998); American Foundation for Urologic Disease (1991-1994); Bob Champion Cancer Trust (2013-present); Research Foundation – Flanders (FWO) [FWO-G.0687.12] (2012-present). E.P. is a European Hematology Association Research Fellow.
dc.languageengen
dc.language.isoenen
dc.subjectAndrogensen
dc.subjectCell Lineageen
dc.subjectClone Cellsen
dc.subjectDNA Mutational Analysisen
dc.subjectDisease Progressionen
dc.subjectEpigenesis, Geneticen
dc.subjectGenes, Tumor Suppressoren
dc.subjectHumansen
dc.subjectMaleen
dc.subjectNeoplasm Metastasisen
dc.subjectProstatic Neoplasmsen
dc.subjectReceptors, Androgenen
dc.subjectSignal Transductionen
dc.titleThe evolutionary history of lethal metastatic prostate canceren
dc.typeArticle
prism.endingPage357
prism.issueIdentifier7547en
prism.publicationDate2015en
prism.publicationNameNatureen
prism.startingPage353
prism.volume520en
dc.identifier.doi10.17863/CAM.13195
dcterms.dateAccepted2015-02-23en
rioxxterms.versionofrecord10.1038/nature14347en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-04-16en
dc.contributor.orcidEaston, Douglas [0000-0003-2444-3247]
dc.identifier.eissn1476-4687
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (via Institute of Cancer Research (ICR)) (C5047/A22530)
pubs.funder-project-idCancer Research UK (via Institute of Cancer Research (ICR)) (C5047/A14835)
cam.issuedOnline2015-04-01en
rioxxterms.freetoread.startdate2015-10-01


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record