title: Genome-wide methylation analysis identifies genes specific to breast cancer hormone receptor status and risk of recurrence.
abstract: To better understand the biology of hormone receptor-positive and-negative breast cancer and to identify methylated gene markers of disease progression, we carried out a genome-wide methylation array analysis on 103 primary invasive breast cancers and 21 normal breast samples, using the Illumina Infinium HumanMethylation27 array that queried 27,578 CpG loci. Estrogen and/or progesterone receptor-positive tumors displayed more hypermethylated loci than estrogen receptor (ER)-negative tumors. However, the hypermethylated loci in ER-negative tumors were clustered closer to the transcriptional start site compared with ER-positive tumors. An ER-classifier set of CpG loci was identified, which independently partitioned primary tumors into ER subtypes. A total of 40 (32 novel and 8 previously known) CpG loci showed differential methylation specific to either ER-positive or ER-negative tumors. Each of the 40 ER subtype-specific loci was validated in silico, using an independent, publicly available methylome dataset from the Cancer Genome Atlas. In addition, we identified 100 methylated CpG loci that were significantly associated with disease progression; the majority of these loci were informative particularly in ER-negative breast cancer. Overall, the set was highly enriched in homeobox containing genes. This pilot study shows the robustness of the breast cancer methylome and illustrates its potential to stratify and reveal biological differences between ER subtypes of breast cancer. Furthermore, it defines candidate ER-specific markers and identifies potential markers predictive of outcome within ER subgroups.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Fackler
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Umbricht
authors.forename: Danielle
authors.initials: D
authors.lastname: Williams
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Leigh-Ann
authors.initials: LA
authors.lastname: Cruz
authors.forename: Vanessa F
authors.initials: VF
authors.lastname: Merino
authors.forename: Wei Wen
authors.initials: WW
authors.lastname: Teo
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Kala
authors.initials: K
authors.lastname: Visvananthan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Marks
authors.forename: Stephen
authors.initials: S
authors.lastname: Ethier
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Cope
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D052138:Genes, Neoplasm; D055106:Genome-Wide Association Study; D006801:Humans; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen