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dc.contributor.authorSchwarz, Roland Fen
dc.contributor.authorNg, Charlotteen
dc.contributor.authorCooke, Susanna Len
dc.contributor.authorNewmann, Scotten
dc.contributor.authorTemple, Jillianen
dc.contributor.authorPiskorz, Annaen
dc.contributor.authorGale, Davinaen
dc.contributor.authorSayal, Karenen
dc.contributor.authorMurtaza, Muhammeden
dc.contributor.authorBaldwin, Peter Jen
dc.contributor.authorRosenfeld, Nitzanen
dc.contributor.authorEarl, Helenaen
dc.contributor.authorSala, Evisen
dc.contributor.authorJimenez-Linan, Mercedesen
dc.contributor.authorParkinson, Christine Aen
dc.contributor.authorMarkowetz, Florianen
dc.contributor.authorBrenton, Jamesen
dc.identifier.citationPLOS Medicine, 2015, DOI:10.1371/journal.pmed.1001789en
dc.description.abstractBackground The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease. Methods and Findings Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22–46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66–1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy. Conclusions This study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse.
dc.description.sponsorshipThis work was supported by Cancer Research UK [grant numbers A15601, A17197, A18072]; the University of Cambridge; National Institute for Health Research Cambridge Biomedical Research Centre; Cambridge Experimental Cancer Medicine Centre and Hutchison Whampoa Limited. CAP was supported in part by the Academy of Medical Sciences, the Wellcome Trust, British Heart Foundation and Arthritis Research UK. The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre.
dc.rightsAttribution 2.0 UK: England & Wales*
dc.subjectGenome evolutionen
dc.subjectPhylogenetic analysisen
dc.subjectEvolutionary geneticsen
dc.subjectCancer treatmenten
dc.subjectGenomic medicineen
dc.subjectOvarian canceren
dc.subjectNeurofibromatosis type 1en
dc.titleSpatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic reconstructionen
dc.description.versionThis is the final published version of a paper first published in PLOS Medicine, 2015, DOI:10.1371/journal.pmed.1001789en
prism.publicationNamePLOS Medicineen
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderArthritis Research UK
dc.contributor.orcidGale, Davina [0000-0002-4521-8199]
dc.contributor.orcidRosenfeld, Nitzan [0000-0002-2825-4788]
dc.contributor.orcidEarl, Helena [0000-0003-1549-8094]
dc.contributor.orcidSala, Evis [0000-0002-5518-9360]
dc.contributor.orcidMarkowetz, Florian [0000-0002-2784-5308]
dc.contributor.orcidBrenton, James [0000-0002-5738-6683]
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (C14303_do not transfer)
pubs.funder-project-idCancer Research UK (CB4320)
pubs.funder-project-idCancer Research UK (CRUK-A15601)

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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales