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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.

journal_name

Mol Oncol

journal_title

Molecular oncology

authors

Kamalakaran S,Varadan V,Giercksky Russnes HE,Levy D,Kendall J,Janevski A,Riggs M,Banerjee N,Synnestvedt M,Schlichting E,Kåresen R,Shama Prasada K,Rotti H,Rao R,Rao L,Eric Tang MH,Satyamoorthy K,Lucito R,Wigler M,Dim

doi

10.1016/j.molonc.2010.11.002

subject

Has Abstract

pub_date

2011-02-01 00:00:00

pages

77-92

issue

eissn

1574-7891

issn

1878-0261

pii

S1574-7891(10)00126-2

journal_volume

pub_type

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DNA methylation patterns in luminal breast cancers differ from non-luminal subtypes and can identify relapse risk independent of other clinical variables.