Understanding the progression of melanocytic neoplasia using genomic analysis: from fields to cancer

Analysis of DNA copy number changes using comparative genomic hybridization in melanocytic neoplasms has revealed distinct patterns of chromosomal aberrations between benign melanocytic nevi and melanoma. Whereas the vast majority of melanoma expresses chromosomal aberrations, blue nevi, congenital nevi, and most Spitz nevi typically show no aberrations. A subset of Spitz nevi shows an isolated gain of chromosome 11p, an aberration pattern not observed in melanoma. These Spitz nevi frequently harbor mutations in the HRAS gene located on this chromosomal arm. Comparisons among melanoma types showed that melanomas of the palms, soles, and subungual sites can be distinguished by the presence of multiple gene amplifications that arise very early in their progression. About 50% of these amplifications are found at the cyclin D1 locus. By contrast, amplifications are significantly less frequent in other cutaneous melanoma types and if present arise late in progression. The frequent amplifications in melanomas on acral sites allowed the detection of single basal melanocytes with gene amplifications in the histologically normal appearing skin immediately adjacent to a melanoma. These field cells represent subtle melanoma in situ and are likely to represent minimal residual disease that can lead to local recurrences if not excised with safety margins. The high frequency of chromosomal aberrations in melanomas and their relative absence in nevi could indicate that melanocytes of melanomas went through telomeric crisis, whereas melanocytes in nevi did not. Such a scenario would suggest that replicative senescence is a tumor-suppressive mechanism in melanocytic neoplasia. It might also explain part of the phenomenon of regression commonly seen in melanoma. Genomic analysis is a powerful tool to obtain insight in the progression of melanocytic neoplasms with potential clinical applications for classification and detection of minimal residual melanoma.