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 Dimitrova & 3 others Bjorn Naume, Anne Lise Borresen-Dale, James B. Hicks

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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.",
    author = "Sitharthan Kamalakaran and Vinay Varadan and {Giercksky Russnes}, {Hege E.} and Dan Levy and Jude Kendall and Angel Janevski and Michael Riggs and Nilanjana Banerjee and Marit Synnestvedt and Ellen Schlichting and Rolf K{\aa}resen and {Shama Prasada}, K. and Harish Rotti and Ramachandra Rao and Laxmi Rao and {Eric Tang}, {Man Hung} and K. Satyamoorthy and Robert Lucito and Michael Wigler and Nevenka Dimitrova and Bjorn Naume and Borresen-Dale, {Anne Lise} and Hicks, {James B.}",
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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

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    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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