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dc.contributor.authorBatra, Rajbir Nath
dc.contributor.authorLifshitz, Aviezer
dc.contributor.authorVidakovic, Ana Tufegdzic
dc.contributor.authorChin, Suet-Feung
dc.contributor.authorSati-Batra, Ankita
dc.contributor.authorSammut, Stephen-John
dc.contributor.authorProvenzano, Elena
dc.contributor.authorAli, H Raza
dc.contributor.authorDariush, Ali
dc.contributor.authorBruna, Alejandra
dc.contributor.authorMurphy, Leigh
dc.contributor.authorPurushotham, Arnie
dc.contributor.authorEllis, Ian
dc.contributor.authorGreen, Andrew
dc.contributor.authorGarrett-Bakelman, Francine E
dc.contributor.authorMason, Chris
dc.contributor.authorMelnick, Ari
dc.contributor.authorAparicio, Samuel AJR
dc.contributor.authorRueda, Oscar M
dc.contributor.authorTanay, Amos
dc.contributor.authorCaldas, Carlos
dc.date.accessioned2021-11-06T00:31:10Z
dc.date.available2021-11-06T00:31:10Z
dc.date.issued2021-09-13
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330373
dc.description.abstractDNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.
dc.languageeng
dc.publisherNature Research
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectBreast Neoplasms
dc.subjectCohort Studies
dc.subjectCpG Islands
dc.subjectDNA Methylation
dc.subjectDNA Replication
dc.subjectEpigenesis, Genetic
dc.subjectEpigenomics
dc.subjectFemale
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectGenome, Human
dc.subjectGenomic Instability
dc.subjectGenomics
dc.subjectHumans
dc.subjectMCF-7 Cells
dc.subjectMutation
dc.subjectPromoter Regions, Genetic
dc.subjectSurvival Analysis
dc.titleDNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation.
dc.typeArticle
prism.endingPage5406
prism.issueIdentifier1
prism.publicationNameNature Communications
prism.startingPage5406
prism.volume12
dc.identifier.doi10.17863/CAM.77816
dcterms.dateAccepted2021-08-18
rioxxterms.versionofrecord10.1038/s41467-021-25661-w
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-08-18
dc.contributor.orcidChin, Suet-Feung [0000-0001-5697-1082]
dc.contributor.orcidSammut, Stephen [0000-0003-4472-904X]
dc.contributor.orcidAli, Raza [0000-0001-7587-0906]
dc.contributor.orcidRueda Palacio, Oscar [0000-0003-0008-4884]
dc.contributor.orcidCaldas, Carlos [0000-0003-3547-1489]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idEuropean Research Council (694620)
pubs.funder-project-idWellcome Trust (106566/Z/14/Z)
pubs.funder-project-idCancer Research UK (C9545/A29580_do not transfer)
pubs.funder-project-idCancer Research UK (25815)
pubs.funder-project-idCancer Research UK (C14303/A17197)
pubs.funder-project-idMedical Research Council (MR/P012442/1)
cam.issuedOnline2021-09-13


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International