Integrative genomics identifies gene signature associated with melanoma ulceration

PLoS One. 2013;8(1):e54958. doi: 10.1371/journal.pone.0054958. Epub 2013 Jan 30.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CpG Islands / genetics
  • DNA Copy Number Variations / genetics
  • DNA Methylation / genetics
  • Female
  • Gene Expression Profiling*
  • Genomics*
  • Humans
  • Male
  • Melanoma / genetics*
  • Melanoma / pathology*
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic / genetics
  • Ulcer / genetics*
  • Young Adult

Grant support

This work was supported by the Hungarian National Research Fund (OTKA K75191), the National Research and Development Program of Hungary (NKFP1-00003/2005), the Hungarian Medical Research Council (193/09-ETT), the Hungarian Academy of Sciences (grant number 2011 TKI 473), by the TÁMOP 4.2.1/B-09/1/KONV-2010-0007 and TÁMOP-4.2.2.A-11/1/KONV-2012-0031 projects; the TÁMOP projects are co-financed by the European Union and the European Social Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.