title: DNA methylation patterns in luminal breast cancers differ from non-luminal subtypes and can identify relapse risk independent of other clinical variables.
abstract: The diversity of breast cancers reflects variations in underlying biology and affects the clinical implications for patients. Gene expression studies have identified five major subtypes- Luminal A, Luminal B, basal-like, ErbB2+ and Normal-Like. We set out to determine the role of DNA methylation in subtypes by performing genome-wide scans of CpG methylation in breast cancer samples with known expression-based subtypes. Unsupervised hierarchical clustering using a set of most varying loci clustered the tumors into a Luminal A majority (82%) cluster, Basal-like/ErbB2+ majority (86%) cluster and a non-specific cluster with samples that were also inconclusive in their expression-based subtype correlations. Contributing methylation loci were both gene associated loci (30%) and non-gene associated (70%), suggesting subtype dependant genome-wide alterations in the methylation landscape. The methylation patterns of significant differentially methylated genes in luminal A tumors are similar to those identified in CD24 + luminal epithelial cells and the patterns in basal-like tumors similar to CD44 + breast progenitor cells. CpG islands in the HOXA cluster and other homeobox (IRX2, DLX2, NKX2-2) genes were significantly more methylated in Luminal A tumors. A significant number of genes (2853, p < 0.05) exhibited expression-methylation correlation, implying possible functional effects of methylation on gene expression. Furthermore, analysis of these tumors by using follow-up survival data identified differential methylation of islands proximal to genes involved in Cell Cycle and Proliferation (Ki-67, UBE2C, KIF2C, HDAC4), angiogenesis (VEGF, BTG1, KLF5), cell fate commitment (SPRY1, OLIG2, LHX2 and LHX5) as having prognostic value independent of subtypes and other clinical factors.
authors.affiliation: Philips Research North America, Biomedical Informatics, Briarcliff Manor, NY 10510, United States. sitharthk@philips.com
authors.forename: Sitharthan
authors.initials: S
authors.lastname: Kamalakaran
authors.forename: Vinay
authors.initials: V
authors.lastname: Varadan
authors.forename: Hege E
authors.initials: HE
authors.lastname: Giercksky Russnes
authors.forename: Dan
authors.initials: D
authors.lastname: Levy
authors.forename: Jude
authors.initials: J
authors.lastname: Kendall
authors.forename: Angel
authors.initials: A
authors.lastname: Janevski
authors.forename: Michael
authors.initials: M
authors.lastname: Riggs
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Banerjee
authors.forename: Marit
authors.initials: M
authors.lastname: Synnestvedt
authors.forename: Ellen
authors.initials: E
authors.lastname: Schlichting
authors.forename: Rolf
authors.initials: R
authors.lastname: Kåresen
authors.forename: K
authors.initials: K
authors.lastname: Shama Prasada
authors.forename: Harish
authors.initials: H
authors.lastname: Rotti
authors.forename: Ramachandra
authors.initials: R
authors.lastname: Rao
authors.forename: Laxmi
authors.initials: L
authors.lastname: Rao
authors.forename: Man-Hung
authors.initials: MH
authors.lastname: Eric Tang
authors.forename: K
authors.initials: K
authors.lastname: Satyamoorthy
authors.forename: Robert
authors.initials: R
authors.lastname: Lucito
authors.forename: Michael
authors.initials: M
authors.lastname: Wigler
authors.forename: Nevenka
authors.initials: N
authors.lastname: Dimitrova
authors.forename: Bjorn
authors.initials: B
authors.lastname: Naume
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Borresen-Dale
authors.forename: James B
authors.initials: JB
authors.lastname: Hicks
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D006801:Humans; D009687:Nuclear Proteins; D011379:Prognosis; D012008:Recurrence; D014157:Transcription Factors