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

Sitharthan Kamalakaran, Vinay Varadan, Hege E. Giercksky Russnes, Dan Levy, Jude Kendall, Angel Janevski, Michael Riggs, Nilanjana Banerjee, Marit Synnestvedt, Ellen Schlichting, Rolf Kåresen, K. Shama Prasada, Harish Rotti, Ramachandra Rao, Laxmi Rao, Man Hung Eric Tang, K. Satyamoorthy, Robert Lucito, Michael Wigler, Nevenka DimitrovaBjorn Naume, Anne Lise Borresen-Dale, James B. Hicks

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)77-92
Number of pages16
JournalMolecular Oncology
Volume5
Issue number1
DOIs
Publication statusPublished - 2011

Fingerprint

DNA Methylation
Methylation
Breast Neoplasms
Recurrence
Genes
Neoplasms
Genome
Gene Expression
CpG Islands
Homeobox Genes
Islands
Vascular Endothelial Growth Factor A
Cluster Analysis
Cell Cycle
Breast
Stem Cells
Epithelial Cells
Cell Proliferation
Survival

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Cancer Research

Cite this

Kamalakaran, Sitharthan ; Varadan, Vinay ; Giercksky Russnes, Hege E. ; Levy, Dan ; Kendall, Jude ; Janevski, Angel ; Riggs, Michael ; Banerjee, Nilanjana ; Synnestvedt, Marit ; Schlichting, Ellen ; Kåresen, Rolf ; Shama Prasada, K. ; Rotti, Harish ; Rao, Ramachandra ; Rao, Laxmi ; Eric Tang, Man Hung ; Satyamoorthy, K. ; Lucito, Robert ; Wigler, Michael ; Dimitrova, Nevenka ; Naume, Bjorn ; Borresen-Dale, Anne Lise ; Hicks, James B. / DNA methylation patterns in luminal breast cancers differ from non-luminal subtypes and can identify relapse risk independent of other clinical variables. In: Molecular Oncology. 2011 ; Vol. 5, No. 1. pp. 77-92.
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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.",
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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, Dimitrova, N, Naume, B, Borresen-Dale, AL & Hicks, JB 2011, 'DNA methylation patterns in luminal breast cancers differ from non-luminal subtypes and can identify relapse risk independent of other clinical variables', Molecular Oncology, vol. 5, no. 1, pp. 77-92. https://doi.org/10.1016/j.molonc.2010.11.002

DNA methylation patterns in luminal breast cancers differ from non-luminal subtypes and can identify relapse risk independent of other clinical variables. / Kamalakaran, Sitharthan; Varadan, Vinay; Giercksky Russnes, Hege E.; Levy, Dan; Kendall, Jude; Janevski, Angel; Riggs, Michael; Banerjee, Nilanjana; Synnestvedt, Marit; Schlichting, Ellen; Kåresen, Rolf; Shama Prasada, K.; Rotti, Harish; Rao, Ramachandra; Rao, Laxmi; Eric Tang, Man Hung; Satyamoorthy, K.; Lucito, Robert; Wigler, Michael; Dimitrova, Nevenka; Naume, Bjorn; Borresen-Dale, Anne Lise; Hicks, James B.

In: Molecular Oncology, Vol. 5, No. 1, 2011, p. 77-92.

Research output: Contribution to journalArticle

TY - JOUR

T1 - DNA methylation patterns in luminal breast cancers differ from non-luminal subtypes and can identify relapse risk independent of other clinical variables

AU - Kamalakaran, Sitharthan

AU - Varadan, Vinay

AU - Giercksky Russnes, Hege E.

AU - Levy, Dan

AU - Kendall, Jude

AU - Janevski, Angel

AU - Riggs, Michael

AU - Banerjee, Nilanjana

AU - Synnestvedt, Marit

AU - Schlichting, Ellen

AU - Kåresen, Rolf

AU - Shama Prasada, K.

AU - Rotti, Harish

AU - Rao, Ramachandra

AU - Rao, Laxmi

AU - Eric Tang, Man Hung

AU - Satyamoorthy, K.

AU - Lucito, Robert

AU - Wigler, Michael

AU - Dimitrova, Nevenka

AU - Naume, Bjorn

AU - Borresen-Dale, Anne Lise

AU - Hicks, James B.

PY - 2011

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N2 - 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.

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