title: A new 12-gene diagnostic biomarker signature of melanoma revealed by integrated microarray analysis.
abstract: Genome-wide microarray technology has facilitated the systematic discovery of diagnostic biomarkers of cancers and other pathologies. However, meta-analyses of published arrays often uncover significant inconsistencies that hinder advances in clinical practice. Here we present an integrated microarray analysis framework, based on a genome-wide relative significance (GWRS) and genome-wide global significance (GWGS) model. When applied to five microarray datasets on melanoma published between 2000 and 2011, this method revealed a new signature of 200 genes. When these were linked to so-called 'melanoma driver' genes involved in MAPK, Ca(2+), and WNT signaling pathways we were able to produce a new 12-gene diagnostic biomarker signature for melanoma (i.e., EGFR, FGFR2, FGFR3, IL8, PTPRF, TNC, CXCL13, COL11A1, CHP2, SHC4, PPP2R2C, and WNT4). We have begun to experimentally validate a subset of these genes involved in MAPK signaling at the protein level, including CXCL13, COL11A1, PTPRF and SHC4 and found these to be over-expressed in metastatic and primary melanoma cells in vitro and in situ compared to melanocytes cultured from healthy skin epidermis and normal healthy human skin. While SHC4 has been reported previously to be associated to melanoma, this is the first time CXCL13, COL11A1, and PTPRF have been associated with melanoma on experimental validation. Our computational evaluation indicates that this 12-gene biomarker signature achieves excellent diagnostic power in distinguishing metastatic melanoma from normal skin and benign nevus. Further experimental validation of the role of these 12 genes in a new signaling network may provide new insights into the underlying biological mechanisms driving the progression of melanoma.
authors: Department of Computing, University of Bradford , Great Britain ; Centre of Skin Sciences, University of Bradford , Great Britain.
authors: Wanting
authors: W
authors: Liu
authors: Yonghong
authors: Y
authors: Peng
authors: Desmond J
authors: DJ
authors: Tobin
keywords: Bioinformatics; Gene biomarker; Genome; Immunochemistry; Melanocytes; Melanoma; Metastasis; Microarray; Nevi; Skin
references: Hum Mutat. 2007 Jun;28(6):578-88
references: 17295241
references: Expert Opin Ther Targets. 2009 Jan;13(1):93-104
references: 19063709
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D109-14
references: 22080510
references: J Invest Dermatol. 2013 Feb;133(2):509-17
references: 22931913
references: Cancer. 2010 Nov 1;116(21):4902-13
references: 20629085
references: N Engl J Med. 2006 Jul 6;355(1):51-65
references: 16822996
references: Cancer Res. 2004 Aug 1;64(15):5270-82
references: 15289333
references: Hum Genomics. 2011 Oct;5(6):538-68
references: 22155603
references: Clin Cancer Res. 2008 Aug 15;14(16):5173-80
references: 18698035
references: BMC Genomics. 2007 Mar 30;8:88
references: 17397532
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D1002-4
references: 21071405
references: Int J Cancer. 2012 Jul 15;131(2):387-95
references: 21964766
references: Development. 2011 Aug;138(16):3579-89
references: 21771814
references: Pigment Cell Res. 2007 Dec;20(6):466-84
references: 17935490
references: Clin Cancer Res. 2007 Feb 1;13(3):806-15
references: 17289871
references: J Invest Dermatol. 2012 Feb;132(2):274-83
references: 21956122
references: Cancer Res. 2002 Aug 1;62(15):4427-33
references: 12154050
references: Mod Pathol. 2012 Jun;25(6):828-37
references: 22411186
references: Int J Cell Biol. 2012;2012:340296
references: 22272201
references: PLoS One. 2011;6(8):e24064
references: 21887372
references: Development. 2011 Apr;138(7):1433-44
references: 21385768
references: Clin Exp Metastasis. 2010 Aug;27(6):371-87
references: 20177751
references: Cancer Biol Ther. 2005 Sep;4(9):1018-29
references: 16251803
references: Diabetes Educ. 2008 Sep-Oct;34(5):815-23
references: 18832286
references: Crit Rev Oncol Hematol. 2009 Dec;72(3):194-214
references: 19328713
references: Prog Biophys Mol Biol. 2011 Dec;107(3):323-32
references: 21875613
references: Immunology. 2009 Jul;127(3):365-72
references: 19191904
references: J Adolesc Health. 2012 Mar;50(3):308-10
references: 22325138
references: BMC Med Genomics. 2008 Apr 28;1:13
references: 18442402
references: Br J Nurs. 2008 Mar 13-26;17(5):300-5
references: 18414292
references: Nature. 2000 Aug 3;406(6795):536-40
references: 10952317
references: Bioinformatics. 2008 Feb 1;24(3):374-82
references: 18204063
references: Bioinformatics. 2003;19 Suppl 1:i84-90
references: 12855442
references: Clin Cancer Res. 2004 May 1;10(9):2922-7
references: 15131026
references: PLoS Med. 2008 Sep 30;5(9):e184
references: 18767902
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D1005-10
references: 21097893
references: Int J Mol Sci. 2011;12(3):1505-18
references: 21673904
references: J Invest Dermatol. 2006 Jan;126(1):154-60
references: 16417231
references: N Engl J Med. 2012 Mar 8;366(10):925-31
references: 22397654
references: Cancer Res. 2007 Apr 1;67(7):3064-73
references: 17409413
references: Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):262-7
references: 10618406
references: Genome Biol. 2003;4(10):R70
references: 14519205
references: Pigment Cell Melanoma Res. 2010 Jun;23(3):394-403
references: 20236442
references: Nat Biotechnol. 2010 Apr;28(4):322-4
references: 20379172
references: Nat Rev Cancer. 2007 Apr;7(4):295-308
references: 17384584
references: CA Cancer J Clin. 2000 Jul-Aug;50(4):215-36; quiz 237-40
references: 10986965
references: Nature. 2005 Jul 7;436(7047):117-22
references: 16001072
references: Front Radiat Ther Oncol. 2006;39:149-158
references: 16394678
references: Cancer Res. 2011 Apr 1;71(7):2561-71
references: 21343389
references: Int J Cancer. 2010 Apr 15;126(8):1869-1881
references: 19795447
references: Bioinformatics. 2008 Jan 15;24(2):258-64
references: 18024475
references: Carcinogenesis. 2012 Apr;33(4):740-50
references: 22287561
references: Oncogene. 2010 Jan 14;29(2):227-36
references: 19802003