A cardinal feature of malignant melanoma is its metastatic propensity. An 
incomplete view of the genetic events driving metastatic progression has been a 
major barrier to rational development of effective therapeutics and prognostic 
diagnostics for melanoma patients. In this study, we conducted global genomic 
characterization of primary and metastatic melanomas to examine the genomic 
landscape associated with metastatic progression. In addition to uncovering 
three genomic subclasses of metastastic melanomas, we delineated 39 focal and 
recurrent regions of amplification and deletions, many of which encompassed 
resident genes that have not been implicated in cancer or metastasis. To 
identify progression-associated metastasis gene candidates, we applied a 
statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic 
regions of interest that were significantly altered in metastatic relative to 
primary melanomas, encompassing 30 resident genes with statistically significant 
expression deregulation. Functional assays on a subset of these candidates, 
including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their 
pro-invasion activities in human melanoma cells. Validity of the IGC approach 
was further reinforced by tissue microarray analysis of Survivin showing 
significant increased protein expression in thick versus thin primary cutaneous 
melanomas, and a progression correlation with lymph node metastases. Together, 
these functional validation results and correlative analysis of human tissues 
support the thesis that integrated genomic and pathological analyses of staged 
melanomas provide a productive entry point for discovery of melanoma metastases 
genes.