title: A DNA methylation-based definition of biologically distinct breast cancer subtypes.
abstract: 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.
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia 08908, Spain.
authors.forename: Olafur A
authors.initials: OA
authors.lastname: Stefansson
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia 08908, Spain.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia 08908, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia 08908, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Sayols
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia 08908, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Arribas-Jorba
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia 08908, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Sandoval
authors.affiliation: The Cancer Research Laboratory, Medical Faculty, University of Iceland, Reykjavik, Iceland.
authors.forename: Holmfridur
authors.initials: H
authors.lastname: Hilmarsdottir
authors.affiliation: The Icelandic Cancer Registry, Reykjavik, Iceland.
authors.forename: Elinborg
authors.initials: E
authors.lastname: Olafsdottir
authors.affiliation: The Icelandic Cancer Registry, Reykjavik, Iceland.
authors.forename: Laufey
authors.initials: L
authors.lastname: Tryggvadottir
authors.affiliation: The Icelandic Cancer Registry, Reykjavik, Iceland; Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: Jon G
authors.initials: JG
authors.lastname: Jonasson
authors.affiliation: The Cancer Research Laboratory, Medical Faculty, University of Iceland, Reykjavik, Iceland.
authors.forename: Jorunn
authors.initials: J
authors.lastname: Eyfjord
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia 08908, Spain; Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain. Electronic address: mesteller@idibell.cat.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D015894:Genome, Human; D006801:Humans; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D015203:Reproducibility of Results
keywords: Biological subtypes; Breast cancer; DNA methylation; Microarrays; Prognosis