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The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma.

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cam.depositDate2022-01-25
cam.issuedOnline2022-04-10
cam.orpheus.counter5
cam.orpheus.successMon Apr 25 18:24:08 BST 2022 - Embargo updated
datacite.isderivedfrom.doi10.1101/2021.05.05.440631
dc.contributor.authorCheng, Zhao
dc.contributor.authorMirza, Hasan
dc.contributor.authorEnnis, Darren P
dc.contributor.authorSmith, Philip
dc.contributor.authorMorrill Gavarró, Lena
dc.contributor.authorSokota, Chishimba
dc.contributor.authorGiannone, Gaia
dc.contributor.authorGoranova, Theodora
dc.contributor.authorBradley, Thomas
dc.contributor.authorPiskorz, Anna
dc.contributor.authorLockley, Michelle
dc.contributor.authorBriTROC-1 Investigators
dc.contributor.authorKaur, Baljeet
dc.contributor.authorSingh, Naveena
dc.contributor.authorTookman, Laura A
dc.contributor.authorKrell, Jonathan
dc.contributor.authorMcDermott, Jacqueline
dc.contributor.authorMacintyre, Geoffrey
dc.contributor.authorMarkowetz, Florian
dc.contributor.authorBrenton, James D
dc.contributor.authorMcNeish, Iain A
dc.contributor.orcidCheng, Zhao [0000-0002-3514-240X]
dc.contributor.orcidMirza, Hasan [0000-0002-6460-5290]
dc.contributor.orcidSmith, Philip [0000-0002-9306-1747]
dc.contributor.orcidMorrill Gavarró, Lena [0000-0002-2242-4010]
dc.contributor.orcidBradley, Thomas [0000-0003-0218-5021]
dc.contributor.orcidLockley, Michelle [0000-0002-9281-5789]
dc.contributor.orcidMacintyre, Geoffrey [0000-0003-3906-467X]
dc.contributor.orcidMarkowetz, Florian [0000-0002-2784-5308]
dc.contributor.orcidBrenton, James D [0000-0002-5738-6683]
dc.contributor.orcidMcNeish, Iain A [0000-0002-9387-7586]
dc.date.accessioned2022-01-27T00:30:05Z
dc.date.available2022-01-27T00:30:05Z
dc.date.issued2022-07-01
dc.date.updated2022-01-25T14:07:58Z
dc.description.abstractPURPOSE: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. EXPERIMENTAL DESIGN: We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I-IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. RESULTS: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. CONCLUSIONS: Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. See related commentary by Yang et al., p. 2730.
dc.identifier.doi10.17863/CAM.80371
dc.identifier.eissn1557-3265
dc.identifier.issn1078-0432
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332946
dc.language.isoeng
dc.publisherAmerican Association for Cancer Research (AACR)
dc.publisher.urlhttp://dx.doi.org/10.1158/1078-0432.ccr-21-1643
dc.rightsAll Rights Reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.subjectCarcinoma, Ovarian Epithelial
dc.subjectFemale
dc.subjectGenomics
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectHumans
dc.subjectMiddle Aged
dc.subjectMutation
dc.subjectOvarian Neoplasms
dc.titleThe Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma.
dc.typeArticle
dcterms.dateAccepted2022-01-24
prism.publicationNameClin Cancer Res
pubs.funder-project-idCancer Research UK (CB4320)
pubs.funder-project-idCancer Research UK (C14303/A17197)
pubs.funder-project-idRoyal Society (WM170023)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (766030)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/R006563/1)
pubs.funder-project-idInnovate UK (74918)
pubs.funder-project-idAlan Turing Institute (TUR-000346)
pubs.funder-project-idCancer Research UK (A22905)
pubs.funder-project-idCancer Research UK (A15973)
pubs.funder-project-idCancer Research UK (A11592)
pubs.funder-project-idCancer Research UK (A15601)
pubs.funder-project-idCancer Research UK (A19274)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1158/1078-0432.CCR-21-1643

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