title: Luminal B breast cancer subtype displays a dicotomic epigenetic pattern.
abstract: Luminal B breast tumors have aggressive clinical and biological features, and constitute the most heterogeneous molecular subtype, both clinically and molecularly. Unfortunately, the immunohistochemistry correlate of the luminal B subtype remains still imprecise, and it has now become of paramount importance to define a classification scheme capable of segregating luminal tumors into clinically meaningful subgroups that may be used clinically to guide patient management. With the aim of unraveling the DNA methylation profiles of the luminal subtypes currently being most used in the clinical setting, we have quantified the DNA methylation level of 27,578 CpG sites in 17 luminal B (ER+, Ki67 ≥ 20 % or PgR < 20 % and HER2-), 8 luminal A (ER+ and Ki67 > 20 %) and 4 luminal B-HER2+ (ER+ and HER2+) breast cancer samples by using the Illumina Infinium methylation microarray approach. Unsupervised hierarchical clustering revealed that DNA methylation stratifies luminal B samples in two categories with differing epigenetic and clinical features. One subgroup of luminal B samples showed a methylator phenotype and clustered with the lumB-HER tumors, while the other showed less methylated events, clustered with the luminal A. A 3 CpG marker panel capable of discriminating methylator versus non-methylator luminal B samples was identified and further validated in an independent cohort of patients. Our results provide evidence that DNA methylation and, more specifically, a panel of 3 CpG markers, enables the stratification of luminal B samples in two categories with differing epigenetic and clinical features and support the utilization of this panel for therapeutic stratification of patients with luminal breast cancer.
authors.affiliation: BIOMICs Research Group, Lascaray Research Center, University of the Basque Country (UPV/EHU), Avda. Miguel de Unamuno, 3, 01006 Vitoria-Gasteiz, Spain.
authors.forename: Naiara G
authors.initials: NG
authors.lastname: Bediaga
authors.affiliation: Molecular (Epi)Genetics Laboratory, BioAraba National Health Institute, OSI Araba University Hospital, 01009 Vitoria-Gasteiz, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Beristain
authors.affiliation: Intelligent Systems Group, University of the Basque Country (UPV/EHU), Donostia-San Sebastián, Basque Country Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Calvo
authors.affiliation: Service of Anatomic Pathology, OSI Araba University Hospital, 01009 Vitoria-Gasteiz, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: Viguri
authors.affiliation: Service of Anatomic Pathology, OSI Araba University Hospital, 01009 Vitoria-Gasteiz, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Gutierrez-Corres
authors.affiliation: Service of Anatomic Pathology, Onkologikoa, Paseo Dr. Begiristain 121, 20014 Donostia-San Sebastián, Gipuzkoa Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rezola
authors.affiliation: Service of Anatomic Pathology, Hospital Universitario Donostia, Paseo Dr. Begiristain 107-115, 20014 Donostia-San Sebastián, Gipuzkoa Spain.
authors.forename: Irune
authors.initials: I
authors.lastname: Ruiz-Diaz
authors.affiliation: Service of Anatomic Pathology, OSI Araba University Hospital, 01009 Vitoria-Gasteiz, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Guerra
authors.affiliation: BIOMICs Research Group, Lascaray Research Center, University of the Basque Country (UPV/EHU), Avda. Miguel de Unamuno, 3, 01006 Vitoria-Gasteiz, Spain.
authors.forename: Marian M
authors.initials: MM
authors.lastname: de Pancorbo
keywords: Breast cancer; Epigenetic; Luminal subtypes; Methylation