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.
