Melanoma is a heterogeneous disease. It is believed that 30-50% of melanomas arise in preexisting lesions, although the vast majority of these benign lesions do not give rise to melanoma. The Cancer Genome Project recently identified BRAF as a new oncogene important in melanoma with mutations in ~70% of melanoma samples (Davies, 2002). In my previous laboratory we verified this high mutation frequency in a large panel of uncultured tumors and identified a similar frequency (~80%) in benign and dysplastic nevi (Pollock, 2003). This study identified activation of the MAPK pathway as almost essential for melanocytic proliferation but not sufficient for melanoma tumorigenesis. The challenge remains to identify the genetic events that are responsible for progression of these benign nevi to invasive melanoma.

My laboratory has characterized a panel of 100 cell lines for mutations in all genes currently identified as mutated in melanoma including BRAF, p16, p14ARF, CDK4, PTEN, p53, N-Ras, H-Ras, K-Ras and b-catenin (unpublished data). This panel of cell lines provides a unique renewable resource in which to identify additional genes involved in melanoma progression. Several novel melanoma oncogenes are currently under investigation in my laboratory. Follow up studies include verification of the mutation frequency in uncultured tumors, phenotype/genotype correlations to determine when during progression these mutations occur, functional characterization of the mutations to determine the mechanism by which these mutations are constitutively activating, and investigation of these genes as likely targets for therapy.