title: Integrative genomics identifies gene signature associated with melanoma ulceration.
abstract: BACKGROUND
  Despite the extensive research approaches applied to characterise malignant melanoma, no specific molecular markers are available that are clearly related to the progression of this disease. In this study, our aims were to define a gene expression signature associated with the clinical outcome of melanoma patients and to provide an integrative interpretation of the gene expression -, copy number alterations -, and promoter methylation patterns that contribute to clinically relevant molecular functional alterations.
  
  
  METHODS
  Gene expression profiles were determined using the Affymetrix U133 Plus2.0 array. The NimbleGen Human CGH Whole-Genome Tiling array was used to define CNAs, and the Illumina GoldenGate Methylation platform was applied to characterise the methylation patterns of overlapping genes.
  
  
  RESULTS
  WE IDENTIFIED TWO SUBCLASSES OF PRIMARY MELANOMA: one representing patients with better prognoses and the other being characteristic of patients with unfavourable outcomes. We assigned 1,080 genes as being significantly correlated with ulceration, 987 genes were downregulated and significantly enriched in the p53, Nf-kappaB, and WNT/beta-catenin pathways. Through integrated genome analysis, we defined 150 downregulated genes whose expression correlated with copy number losses in ulcerated samples. These genes were significantly enriched on chromosome 6q and 10q, which contained a total of 36 genes. Ten of these genes were downregulated and involved in cell-cell and cell-matrix adhesion or apoptosis. The expression and methylation patterns of additional genes exhibited an inverse correlation, suggesting that transcriptional silencing of these genes is driven by epigenetic events.
  
  
  CONCLUSIONS
  Using an integrative genomic approach, we were able to identify functionally relevant molecular hotspots characterised by copy number losses and promoter hypermethylation in distinct molecular subtypes of melanoma that contribute to specific transcriptomic silencing and might indicate a poor clinical outcome of melanoma.
authors: Department of Preventive Medicine, Faculty of Public Health, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
authors: Zsuzsa
authors: Z
authors: Rakosy
authors: Szilvia
authors: S
authors: Ecsedi
authors: Reka
authors: R
authors: Toth
authors: Laura
authors: L
authors: Vizkeleti
authors: Hector
authors: H
authors: Hernandez-Vargas
authors: Hector
authors: H
authors: Herandez-Vargas
authors: Viktoria
authors: V
authors: Lazar
authors: Gabriella
authors: G
authors: Emri
authors: Istvan
authors: I
authors: Szatmari
authors: Zdenko
authors: Z
authors: Herceg
authors: Roza
authors: R
authors: Adany
authors: Margit
authors: M
authors: Balazs
mesh_terms: D000328:Adult; D018899:CpG Islands / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D014456:Ulcer / Q000235:genetics*; D055815:Young Adult
references: Pigment Cell Melanoma Res. 2009 Dec;22(6):724-39
references: 19708915
references: Clin Exp Metastasis. 2010 Aug;27(6):371-87
references: 20177751
references: J Natl Cancer Inst. 2006 Apr 5;98(7):472-82
references: 16595783
references: Cancer Control. 2009 Jul;16(3):200-18
references: 19556960
references: Cell Cycle. 2008 Jul 1;7(13):1944-8
references: 18604170
references: Pigment Cell Melanoma Res. 2011 Apr;24(2):352-60
references: 21375697
references: Mol Cancer Res. 2009 Sep;7(9):1438-45
references: 19723875
references: Patholog Res Int. 2011;2011:159421
references: 21876842
references: Cancer Sci. 2004 Dec;95(12):962-8
references: 15596045
references: J Transl Med. 2006 Nov 27;4:50
references: 17129373
references: IEEE/ACM Trans Comput Biol Bioinform. 2012 Jul-Aug;9(4):947-54
references: 21788678
references: J Skin Cancer. 2011;2011:521947
references: 22007305
references: Clin Cancer Res. 2009 Nov 15;15(22):6939-46
references: 19887478
references: Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
references: 12184808
references: Clin Cancer Res. 2007 Feb 1;13(3):806-15
references: 17289871
references: PLoS One. 2010 May 24;5(5):e10770
references: 20520718
references: Am J Pathol. 2011 Jun;178(6):2513-22
references: 21641377
references: Exp Dermatol. 2009 Sep;18(9):750-9
references: 19558497
references: Hematol Oncol Clin North Am. 2009 Jun;23(3):397-414, vii
references: 19464593
references: Cancer Biol Ther. 2005 Sep;4(9):1018-29
references: 16251803
references: Eur J Surg Oncol. 2006 Mar;32(2):218-23
references: 16412599
references: J Clin Invest. 2005 Apr;115(4):813-24
references: 15841168
references: Br J Cancer. 2011 Jan 4;104(1):155-65
references: 21081927
references: Cell. 2001 Jan 12;104(1):9-19
references: 11163236
references: Ann Surg. 2012 Jun;255(6):1165-70
references: 22566014
references: Cancer Res. 2010 Jul 15;70(14):5686-94
references: 20587528
references: Oncogene. 2007 Jul 12;26(32):4738-48
references: 17260012
references: Curr Drug Discov Technol. 2008 Mar;5(1):9-14
references: 18537562
references: Int J Oncol. 2008 Jun;32(6):1343-9
references: 18497997
references: Cancer Res. 2007 Apr 1;67(7):3450-60
references: 17409456
references: Ann Surg Oncol. 2010 Aug;17(8):2006-14
references: 20379784
references: BMC Med Genomics. 2008 Apr 28;1:13
references: 18442402
references: Br J Cancer. 2010 Oct 12;103(8):1229-36
references: 20859289
references: PLoS One. 2010 Mar 17;5(3):e9749
references: 20305825
references: Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6092-7
references: 15833814
references: Clin Dermatol. 2010 May-Jun;28(3):275-80
references: 20541679
references: Nature. 2000 Aug 3;406(6795):536-40
references: 10952317
references: Genes Chromosomes Cancer. 2010 May;49(5):425-38
references: 20140953
references: Oncogene. 2008 Jan 24;27(5):565-73
references: 17891185
references: Genes Chromosomes Cancer. 2010 Aug;49(8):733-45
references: 20544847
references: J Cancer. 2011;2:538-43
references: 22084644
references: Pigment Cell Melanoma Res. 2010 Dec;23(6):763-70
references: 20874733
references: Biom J. 2010 Feb;52(1):70-84
references: 19937997
references: Mod Pathol. 2009 Apr;22(4):538-46
references: 19270649
references: PLoS One. 2009 Dec 24;4(12):e8461
references: 20041153
references: BMC Bioinformatics. 2010 Oct 06;11:495
references: 20925909
references: J Cutan Pathol. 2011 Apr;38(4):329-34
references: 21323721
references: Ann Surg Oncol. 2007 Apr;14(4):1416-23
references: 17195911
references: PLoS One. 2010 Mar 11;5(3):e9651
references: 20300172
references: J Clin Oncol. 2001 Aug 15;19(16):3635-48
references: 11504745
references: BMC Med Genomics. 2011 Oct 27;4:76
references: 22032772
references: Int J Cancer. 2007 Oct 15;121(8):1729-37
references: 17594688
references: Histopathology. 2010 Jan;56(1):121-32
references: 20055910
references: Curr Opin Oncol. 2012 Mar;24(2):137-40
references: 22234255
references: Cancer Genet Cytogenet. 2008 Apr 15;182(2):116-21
references: 18406873
references: Cancer Res. 2011 Apr 1;71(7):2561-71
references: 21343389
references: Cancer Res. 2007 Mar 15;67(6):2632-42
references: 17363583
references: J Clin Oncol. 2009 Dec 20;27(36):6199-206
references: 19917835
references: Melanoma Res. 2010 Aug;20(4):253-65
references: 20418788
references: Mod Pathol. 2005 Apr;18(4):503-10
references: 15475929
references: Cancer Inform. 2007 Feb 08;3:55-63
references: 19455235
references: PLoS One. 2011 Apr 08;6(4):e18369
references: 21494657
references: Recent Results Cancer Res. 2007;176:25-32
references: 17607913