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dc.contributor.authorTaylor-Weiner, A
dc.contributor.authorZack, T
dc.contributor.authorO'Donnell, E
dc.contributor.authorGuerriero, JL
dc.contributor.authorBernard, B
dc.contributor.authorReddy, A
dc.contributor.authorHan, GC
dc.contributor.authorAlDubayan, S
dc.contributor.authorAmin-Mansour, A
dc.contributor.authorSchumacher, SE
dc.contributor.authorLitchfield, K
dc.contributor.authorTurnbull, C
dc.contributor.authorGabriel, S
dc.contributor.authorBeroukhim, R
dc.contributor.authorGetz, G
dc.contributor.authorCarter, SL
dc.contributor.authorHirsch, MS
dc.contributor.authorLetai, A
dc.contributor.authorSweeney, C
dc.contributor.authorVan Allen, EM
dc.date.accessioned2020-09-30T14:32:09Z
dc.date.issued2016-11
dc.identifier.citationNature, 2016, 540 (7631), pp. 114 - 118
dc.identifier.issn0028-0836
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4118
dc.identifier.eissn1476-4687
dc.identifier.doi10.1038/nature20596
dc.description.abstractGerm-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes. GCTs are histologically heterogeneous and distinctly curable with chemotherapy. Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types. These tumours also acquire KRAS mutations during the development from precursor to primary disease, and primary testicular GCTs (TGCTs) are uniformly wild type for TP53. In addition, by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue, we find that primary TGCTs have high mitochondrial priming that facilitates chemotherapy-induced apoptosis. Finally, by phylogenetic analysis of serial TGCTs that emerge with chemotherapy resistance, we show how TGCTs gain additional reciprocal loss of heterozygosity and that this is associated with loss of pluripotency markers (NANOG and POU5F1) in chemoresistant teratomas or transformed carcinomas. Our results demonstrate the distinct genomic features underlying the origins of this disease and associated with the chemosensitivity phenotype, as well as the rare progression to chemoresistance. These results identify the convergence of cancer genomics, mitochondrial priming and GCT evolution, and may provide insights into chemosensitivity and resistance in other cancers.
dc.formatPrint
dc.format.extent114 - 118
dc.languageeng
dc.language.isoeng
dc.subjectMitochondria
dc.subjectHumans
dc.subjectNeoplasms, Germ Cell and Embryonal
dc.subjectTeratoma
dc.subjectTesticular Neoplasms
dc.subjectNeoplasm Metastasis
dc.subjectDisease Progression
dc.subjectGenomics
dc.subjectEvolution, Molecular
dc.subjectPhylogeny
dc.subjectApoptosis
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectLoss of Heterozygosity
dc.subjectGenome, Human
dc.subjectMale
dc.subjectTumor Suppressor Protein p53
dc.subjectProto-Oncogene Proteins p21(ras)
dc.subjectOctamer Transcription Factor-3
dc.subjectTranscriptome
dc.subjectExome
dc.subjectNanog Homeobox Protein
dc.titleGenomic evolution and chemoresistance in germ-cell tumours.
dc.typeJournal Article
dcterms.dateAccepted2016-11-02
rioxxterms.versionofrecord10.1038/nature20596
rioxxterms.licenseref.startdate2016-11
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature
pubs.issue7631
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular & Population Genetics
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular & Population Genetics
pubs.publication-statusPublished
pubs.volume540
pubs.embargo.termsNot known
icr.researchteamMolecular & Population Geneticsen_US
dc.contributor.icrauthorTurnbull, Clareen
dc.contributor.icrauthorLitchfield, Kevinen


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