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Roadmap of DNA methylation in breast cancer identifies novel prognostic biomarkers

dc.contributor.authorAlmeida, Bernardo
dc.contributor.authorApolónio, Joana
dc.contributor.authorBinnie, Alexandra
dc.contributor.authorCastelo-Branco, Pedro
dc.date.accessioned2019-04-02T09:45:25Z
dc.date.available2019-04-02T09:45:25Z
dc.date.issued2019-03-12
dc.date.updated2019-04-01T05:57:09Z
dc.description.abstractBackground Breast cancer is a highly heterogeneous disease resulting in diverse clinical behaviours and therapeutic responses. DNA methylation is a major epigenetic alteration that is commonly perturbed in cancers. The aim of this study is to characterize the relationship between DNA methylation and aberrant gene expression in breast cancer. Methods We analysed DNA methylation and gene expression profiles from breast cancer tissue and matched normal tissue in The Cancer Genome Atlas (TCGA). Genome-wide differential methylation analysis and methylation-gene expression correlation was performed. Gene expression changes were subsequently validated in the METABRIC dataset. The Oncoscore tool was used to identify genes that had previously been associated with cancer in the literature. A subset of genes that had not previously been studied in cancer was chosen for further analysis. Results We identified 368 CpGs that were differentially methylated between tumor and normal breast tissue (∆β > 0.4). Hypermethylated CpGs were overrepresented in tumor tissue and were found predominantly (56%) in upstream promoter regions. Conversely, hypomethylated CpG sites were found primarily in the gene body (66%). Expression analysis revealed that 209 of the differentially-methylated CpGs were located in 169 genes that were differently expressed between normal and breast tumor tissue. Methylation-expression correlations were predominantly negative (70%) for promoter CpG sites and positive (74%) for gene body CpG sites. Among these differentially-methylated and differentially-expressed genes, we identified 7 that had not previously been studied in any form of cancer. Three of these, TDRD10, PRAC2 and TMEM132C, contained CpG sites that showed diagnostic and prognostic value in breast cancer, particularly in estrogen-receptor (ER)-positive samples. A pan-cancer analysis confirmed differential expression of these genes together with diagnostic and prognostic value of their respective CpG sites in multiple cancer types. Conclusion We have identified 368 DNA methylation changes that characterize breast cancer tumor tissue, of which 209 are associated with genes that are differentially-expressed in the same samples. Novel DNA methylation markers were identified, of which cg12374721 (PRAC2), cg18081940 (TDRD10) and cg04475027 (TMEM132C) show promise as diagnostic and prognostic markers in breast cancer as well as other cancer types.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBMC Cancer. 2019 Mar 12;19(1):219pt_PT
dc.identifier.dois12885-019-5403-0pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.1/12432
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherBMCpt_PT
dc.rights.holderThe Author(s).
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleRoadmap of DNA methylation in breast cancer identifies novel prognostic biomarkerspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FBIM%2F04773%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/PD/PD%2FBD%2F105899%2F2014/PT
oaire.citation.issue1pt_PT
oaire.citation.startPage219pt_PT
oaire.citation.titleBMC Cancerpt_PT
oaire.citation.volume19pt_PT
oaire.fundingStream5876
oaire.fundingStreamPD
person.familyNameAlmeida
person.familyNameApolónio
person.familyNameBinnie
person.familyNameCastelo-Branco
person.givenNameBernardo
person.givenNameJoana
person.givenNameAlexandra
person.givenNamePedro
person.identifier.ciencia-id791E-9E39-2795
person.identifier.ciencia-idC212-F6D7-8240
person.identifier.ciencia-idE015-7F8F-5CA1
person.identifier.orcid0000-0002-6084-6775
person.identifier.orcid0000-0002-9727-1813
person.identifier.orcid0000-0003-2969-8177
person.identifier.orcid0000-0002-3453-3978
person.identifier.scopus-author-id7004219471
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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