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Roadmap of DNA methylation in breast cancer identifies novel prognostic biomarkers

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dc.contributor.authorAlmeida, Bernardo P. De
dc.contributor.authorApolónio, Joana Dias
dc.contributor.authorBinnie, Alexandra
dc.contributor.authorCastelo Branco, Pedro
dc.date.accessioned2021-06-08T12:54:58Z
dc.date.available2021-06-08T12:54:58Z
dc.date.issued2019
dc.description© The Author(s). 2019. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.pt_PT
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.sponsorshipThis work was supported by the research grant UID/BIM/04773/2013 CBMR from FCT and Maratona da Saúde. JA is supported by PD/BD/105899/2014 FCT fellowship.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBMC Cancer. 2019 Mar 12;19(1):219pt_PT
dc.identifier.doi10.1186/s12885-019-5403-0pt_PT
dc.identifier.eissn1471-2407
dc.identifier.urihttp://hdl.handle.net/10451/48408
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relation.publisherversionhttps://bmccancer.biomedcentral.com/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectBiomarkerspt_PT
dc.subjectBreast cancerpt_PT
dc.subjectDNA methylationpt_PT
dc.subjectDiagnosticpt_PT
dc.subjectPrognosticpt_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.titleBMC Cancerpt_PT
oaire.citation.volume19pt_PT
oaire.fundingStream5876
oaire.fundingStreamPD
person.familyNameAlmeida
person.givenNameBernardo
person.identifier.orcid0000-0002-6084-6775
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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relation.isAuthorOfPublication.latestForDiscovery4f8f6e90-fda3-4bee-b063-dcd770fa215a
relation.isProjectOfPublication8279804a-bbf8-47ac-a5f5-d5137ba7cb27
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