title: Whole genome DNA methylation signature of HER2-positive breast cancer.
abstract: In order to obtain a comprehensive DNA methylation signature of HER2-positive breast cancer (HER2+ breast cancer), we performed a genome-wide methylation analysis on 17 HER2+ breast cancer and compared with ten normal breast tissue samples using the Illumina Infinium HumanMethylation450 BeadChip (450K). In HER2+ breast cancer, we found altered DNA methylation in genes involved in multicellular development, differentiation and transcription. Within these genes, we observed an overrepresentation of homeobox family genes, including several genes that have not been previously reported in relation to cancer (DBX1, NKX2-6, SIX6). Other affected genes included several belonging to the PI3K and Wnt signaling pathways. Notably, HER2, AKT3, HK1, and PFKP, genes for which altered methylation has not been previously reported, were also identified in this analysis. In total, we report 69 candidate biomarker genes with maximum differential methylation in HER2+ breast cancer. External validation of gene expression in a selected group of these genes (n = 13) revealed lowered mean gene expression in HER2+ breast cancer. We analyzed DNA methylation in six top candidate genes (AKR1B1, INA, FOXC2, NEUROD1, CDKL2, IRF4) using EpiTect Methyl II Custom PCR Array and confirmed the 450K array findings. Future clinical studies focusing on these genes, as well as on homeobox-containing genes and HER2, AKT3, HK1, and PFKP, are warranted which could provide further insights into the biology of HER2+ breast cancer.
authors.affiliation: School of Health and Medical Sciences; Örebro University; Örebro, Sweden.
authors.forename: Breezy M
authors.initials: BM
authors.lastname: Lindqvist
authors.affiliation: School of Health and Medical Sciences; Örebro University; Örebro, Sweden.
authors.forename: Sten
authors.initials: S
authors.lastname: Wingren
authors.affiliation: Department of Medical Biosciences/Clinical Chemistry; Umeå University; Umeå, Sweden.
authors.forename: Parviz B
authors.initials: PB
authors.lastname: Motlagh
authors.affiliation: Department of Medical Biosciences/Clinical Chemistry; Umeå University; Umeå, Sweden.
authors.forename: Torbjörn K
authors.initials: TK
authors.lastname: Nilsson
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005801:Genes, Homeobox; D015894:Genome, Human; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: DNA methylation; HER2-positive breast cancer; Illumina Infinium HumanMethylation450 BeadChip
references.citation: Nat Rev Cancer. 2002 Oct;2(10):777-85
references.pmid: 12360280
references.citation: Science. 1987 Jan 9;235(4785):177-82
references.pmid: 3798106
references.citation: BMC Cancer. 2011 Jun 15;11:248
references.pmid: 21676217
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Int J Cancer. 2004 Nov 10;112(3):407-10
references.pmid: 15382065
references.citation: Clin Cancer Res. 2012 May 15;18(10):2882-95
references.pmid: 22589488
references.citation: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references.pmid: 11252954
references.citation: Nat Rev Cancer. 2010 May;10(5):361-71
references.pmid: 20357775
references.citation: Int J Cancer. 2010 Dec 15;127(12):2893-917
references.pmid: 21351269
references.citation: Mol Cell Biol. 1996 Oct;16(10):5276-87
references.pmid: 8816440
references.citation: Nature. 2010 Sep 16;467(7313):338-42
references.pmid: 20720541
references.citation: Biol Chem. 2003 May;384(5):763-75
references.pmid: 12817473
references.citation: J Biol Chem. 2011 Jul 8;286(27):23808-16
references.pmid: 21586797
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D412-6
references.pmid: 18940858
references.citation: Epigenetics. 2012 Mar;7(3):300-6
references.pmid: 22430806
references.citation: Clin Cancer Res. 2007 Oct 1;13(19):5883-8
references.pmid: 17908983
references.citation: PLoS One. 2012;7(5):e36780
references.pmid: 22615811
references.citation: Eur J Cancer. 2003 Jan;39(2):257-64
references.pmid: 12509959
references.citation: Sci Transl Med. 2012 Aug 22;4(148):148ra117
references.pmid: 22914623
references.citation: Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):903-13
references.pmid: 14967450
references.citation: Biochim Biophys Acta. 2009 Dec;1796(2):114-28
references.pmid: 19344752
references.citation: Breast Cancer Res Treat. 2012 Jun;133(2):583-94
references.pmid: 22002566
references.citation: Science. 1989 May 12;244(4905):707-12
references.pmid: 2470152
references.citation: Science. 2003 Apr 18;300(5618):489-92
references.pmid: 12702876
references.citation: Cancer Lett. 2009 Apr 18;276(2):125-35
references.pmid: 18790562
references.citation: Cell. 2007 Feb 23;128(4):683-92
references.pmid: 17320506
references.citation: Breast Cancer Res. 2010;12(6):213
references.pmid: 21067528
references.citation: Genomics. 2011 Oct;98(4):288-95
references.pmid: 21839163
references.citation: BMC Biol. 2007 Oct 26;5:47
references.pmid: 17963489
references.citation: Prostate. 2012 Oct 1;72(14):1550-8
references.pmid: 22415519
references.citation: J Pathol. 2003 Jul;200(3):290-7
references.pmid: 12845624
references.citation: Oncol Rep. 2012 Jul;28(1):99-104
references.pmid: 22552777
references.citation: Breast Cancer Res Treat. 2009 Jan;113(1):113-21
references.pmid: 18256927
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5527-32
references.pmid: 17369352
references.citation: Science. 1985 Apr 12;228(4696):187-90
references.pmid: 2579435
references.citation: Epigenomics. 2011 Dec;3(6):771-84
references.pmid: 22126295
references.citation: Med Oncol. 2011 Jun;28(2):420-3
references.pmid: 20237868
references.citation: Breast Cancer Res. 2011;13(6):R129
references.pmid: 22169037
references.citation: Cancer Res. 2011 Oct 1;71(19):6195-207
references.pmid: 21825015
references.citation: Gene. 2003 Jan 2;302(1-2):65-72
references.pmid: 12527197
references.citation: Epigenetics Chromatin. 2013 Mar 03;6(1):4
references.pmid: 23452981
references.citation: Br J Biomed Sci. 2000;57(2):170-8
references.pmid: 10912295
references.citation: Bioinformatics. 2012 Mar 1;28(5):729-30
references.pmid: 22253290
references.citation: Cancer Cell. 2004 Aug;6(2):117-27
references.pmid: 15324695
references.citation: Cancer Biol Ther. 2004 Dec;3(12):1225-31
references.pmid: 15539937
references.citation: Epigenetics. 2011 Jun;6(6):692-702
references.pmid: 21593595
references.citation: Cancer Res. 2001 May 15;61(10):4238-43
references.pmid: 11358850
references.citation: Am J Pathol. 2002 Feb;160(2):605-12
references.pmid: 11839581
references.citation: Pathol Res Pract. 2010 Apr 15;206(4):223-8
references.pmid: 20097481
references.citation: Genome Biol. 2013 Sep 24;14(9):r105
references.pmid: 24063430
references.citation: Eur J Cancer. 2005 Jul;41(11):1628-36
references.pmid: 15951164
references.citation: Carcinogenesis. 2009 Mar;30(3):466-71
references.pmid: 19168584