A DNA methylation-based definition of biologically distinct breast cancer subtypes

In cancer, epigenetic states are deregulated and thought to be of significance in cancer development and progression. We explored DNA methylation-based signatures in association with breast cancer subtypes to assess their impact on clinical presentation and patient prognosis. DNA methylation was ana...

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Detalles Bibliográficos
Autores: Stefansson, Olafur A., Moran, Sebastian, Gómez, Antonio, Sayols, Sergi, Arribas, Carles, Sandoval, Juan, Hilmarsdottir, Holmfridur, Olafsdottir, Elinborg, Tryggvadottir, Laufey, Jonasson, Jon G., Eyfjord, Jorunn E., Esteller, Manel, 1968-
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2015
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/178081
Acceso en línea:https://hdl.handle.net/2445/178081
Access Level:acceso abierto
Palabra clave:Càncer de mama
Genètica
ADN
Metilació
Breast cancer
Genetics
DNA
Methylation
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spelling A DNA methylation-based definition of biologically distinct breast cancer subtypesStefansson, Olafur A.Moran, SebastianGómez, AntonioSayols, SergiArribas, CarlesSandoval, JuanHilmarsdottir, HolmfridurOlafsdottir, ElinborgTryggvadottir, LaufeyJonasson, Jon G.Eyfjord, Jorunn E.Esteller, Manel, 1968-Càncer de mamaGenèticaADNMetilacióBreast cancerGeneticsDNAMethylationIn cancer, epigenetic states are deregulated and thought to be of significance in cancer development and progression. We explored DNA methylation-based signatures in association with breast cancer subtypes to assess their impact on clinical presentation and patient prognosis. DNA methylation was analyzed using Infinium 450K arrays in 40 tumors and 17 normal breast samples, together with DNA copy number changes and subtype-specific markers by tissue microarrays. The identified methylation signatures were validated against a cohort of 212 tumors annotated for breast cancer subtypes by the PAM50 method (The Cancer Genome Atlas). Selected markers were pyrosequenced in an independent validation cohort of 310 tumors and analyzed with respect to survival, clinical stage and grade. The results demonstrate that DNA methylation patterns linked to the luminal-B subtype are characterized by CpG island promoter methylation events. In contrast, a large fraction of basal-like tumors are characterized by hypomethylation events occurring within the gene body. Based on these hallmark signatures, we defined two DNA methylation-based subtypes, Epi-LumB and Epi-Basal, and show that they are associated with unfavorable clinical parameters and reduced survival. Our data show that distinct mechanisms leading to changes in CpG methylation states are operative in different breast cancer subtypes. Importantly, we show that a few selected proxy markers can be used to detect the distinct DNA methylation-based subtypes thereby providing valuable information on disease prognosis.Elsevier2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/178081Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1016/j.molonc.2014.10.012Molecular Oncology, 2015, vol. 9, num. 3, p. 555-568https://doi.org/10.1016/j.molonc.2014.10.012(c) Federation of European Biochemical Societies, 2015info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1780812026-05-27T06:46:51Z
dc.title.none.fl_str_mv A DNA methylation-based definition of biologically distinct breast cancer subtypes
title A DNA methylation-based definition of biologically distinct breast cancer subtypes
spellingShingle A DNA methylation-based definition of biologically distinct breast cancer subtypes
Stefansson, Olafur A.
Càncer de mama
Genètica
ADN
Metilació
Breast cancer
Genetics
DNA
Methylation
title_short A DNA methylation-based definition of biologically distinct breast cancer subtypes
title_full A DNA methylation-based definition of biologically distinct breast cancer subtypes
title_fullStr A DNA methylation-based definition of biologically distinct breast cancer subtypes
title_full_unstemmed A DNA methylation-based definition of biologically distinct breast cancer subtypes
title_sort A DNA methylation-based definition of biologically distinct breast cancer subtypes
dc.creator.none.fl_str_mv Stefansson, Olafur A.
Moran, Sebastian
Gómez, Antonio
Sayols, Sergi
Arribas, Carles
Sandoval, Juan
Hilmarsdottir, Holmfridur
Olafsdottir, Elinborg
Tryggvadottir, Laufey
Jonasson, Jon G.
Eyfjord, Jorunn E.
Esteller, Manel, 1968-
author Stefansson, Olafur A.
author_facet Stefansson, Olafur A.
Moran, Sebastian
Gómez, Antonio
Sayols, Sergi
Arribas, Carles
Sandoval, Juan
Hilmarsdottir, Holmfridur
Olafsdottir, Elinborg
Tryggvadottir, Laufey
Jonasson, Jon G.
Eyfjord, Jorunn E.
Esteller, Manel, 1968-
author_role author
author2 Moran, Sebastian
Gómez, Antonio
Sayols, Sergi
Arribas, Carles
Sandoval, Juan
Hilmarsdottir, Holmfridur
Olafsdottir, Elinborg
Tryggvadottir, Laufey
Jonasson, Jon G.
Eyfjord, Jorunn E.
Esteller, Manel, 1968-
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer de mama
Genètica
ADN
Metilació
Breast cancer
Genetics
DNA
Methylation
topic Càncer de mama
Genètica
ADN
Metilació
Breast cancer
Genetics
DNA
Methylation
description In cancer, epigenetic states are deregulated and thought to be of significance in cancer development and progression. We explored DNA methylation-based signatures in association with breast cancer subtypes to assess their impact on clinical presentation and patient prognosis. DNA methylation was analyzed using Infinium 450K arrays in 40 tumors and 17 normal breast samples, together with DNA copy number changes and subtype-specific markers by tissue microarrays. The identified methylation signatures were validated against a cohort of 212 tumors annotated for breast cancer subtypes by the PAM50 method (The Cancer Genome Atlas). Selected markers were pyrosequenced in an independent validation cohort of 310 tumors and analyzed with respect to survival, clinical stage and grade. The results demonstrate that DNA methylation patterns linked to the luminal-B subtype are characterized by CpG island promoter methylation events. In contrast, a large fraction of basal-like tumors are characterized by hypomethylation events occurring within the gene body. Based on these hallmark signatures, we defined two DNA methylation-based subtypes, Epi-LumB and Epi-Basal, and show that they are associated with unfavorable clinical parameters and reduced survival. Our data show that distinct mechanisms leading to changes in CpG methylation states are operative in different breast cancer subtypes. Importantly, we show that a few selected proxy markers can be used to detect the distinct DNA methylation-based subtypes thereby providing valuable information on disease prognosis.
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/178081
url https://hdl.handle.net/2445/178081
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1016/j.molonc.2014.10.012
Molecular Oncology, 2015, vol. 9, num. 3, p. 555-568
https://doi.org/10.1016/j.molonc.2014.10.012
dc.rights.none.fl_str_mv (c) Federation of European Biochemical Societies, 2015
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Federation of European Biochemical Societies, 2015
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301629

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