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dc.contributor.authorFisher, R
dc.contributor.authorHorswell, S
dc.contributor.authorRowan, A
dc.contributor.authorSalm, MP
dc.contributor.authorde Bruin, EC
dc.contributor.authorGulati, S
dc.contributor.authorMcGranahan, N
dc.contributor.authorStares, M
dc.contributor.authorGerlinger, M
dc.contributor.authorVarela, I
dc.contributor.authorCrockford, A
dc.contributor.authorFavero, F
dc.contributor.authorQuidville, V
dc.contributor.authorAndré, F
dc.contributor.authorNavas, C
dc.contributor.authorGrönroos, E
dc.contributor.authorNicol, D
dc.contributor.authorHazell, S
dc.contributor.authorHrouda, D
dc.contributor.authorO'Brien, T
dc.contributor.authorMatthews, N
dc.contributor.authorPhillimore, B
dc.contributor.authorBegum, S
dc.contributor.authorRabinowitz, A
dc.contributor.authorBiggs, J
dc.contributor.authorBates, PA
dc.contributor.authorMcDonald, NQ
dc.contributor.authorStamp, G
dc.contributor.authorSpencer-Dene, B
dc.contributor.authorHsieh, JJ
dc.contributor.authorXu, J
dc.contributor.authorPickering, L
dc.contributor.authorGore, M
dc.contributor.authorLarkin, J
dc.contributor.authorSwanton, C
dc.date.accessioned2020-08-17T15:25:25Z
dc.date.issued2014-08-27
dc.identifier.citationGenome biology, 2014, 15 (8), pp. 433 - ?
dc.identifier.issn1474-7596
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3979
dc.identifier.eissn1474-760X
dc.identifier.doi10.1186/s13059-014-0433-z
dc.description.abstractBackground Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution.Results We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma.Conclusions In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.
dc.formatElectronic
dc.format.extent433 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectChromosomes, Human, Pair 3
dc.subjectHumans
dc.subjectCarcinoma, Renal Cell
dc.subjectKidney Neoplasms
dc.subjectChromosome Deletion
dc.subjectSequence Analysis, DNA
dc.subjectPhylogeny
dc.subjectMAP Kinase Signaling System
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectGenetic Heterogeneity
dc.subjectGerm-Line Mutation
dc.subjectModels, Molecular
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectMale
dc.subjectvon Hippel-Lindau Disease
dc.subjectExome
dc.titleDevelopment of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution.
dc.typeJournal Article
dcterms.dateAccepted2014-08-08
rioxxterms.versionofrecord10.1186/s13059-014-0433-z
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2014-08-27
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfGenome biology
pubs.issue8
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer/Melanoma and Kidney Cancer (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Experimental Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer/Melanoma and Kidney Cancer (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Experimental Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume15
pubs.embargo.termsNot known
icr.researchteamMelanoma and Kidney Canceren_US
icr.researchteamExperimental Pathologyen_US
icr.researchteamTranslational Oncogenomicsen_US
dc.contributor.icrauthorStamp, Gordonen
dc.contributor.icrauthorGerlinger, Marcoen
dc.contributor.icrauthorGore, Martinen
dc.contributor.icrauthorLarkin, Jamesen


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