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

Abstract

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. Oncogene (2003) 22, 3081-3086. doi:10.1038/sj.onc.1206463Keywords: melanoma; Spitz nevus; genetics; regression; minimal residual disease Patterns of chromosomal aberrations in melanocytic neoplasmsWe have used comparative genomic hybridization (CGH) to perform genome-wide searches for patterns of aberrations that may be of help in the classification of melanocytic neoplasms. Using chromosome and arraybased CGH we have analysed several hundreds of benign and malignant melanocytic skin tumors. CGH can detect and map changes in DNA copy number in DNA samples including DNA extracted from archival specimens. Whereas the vast majority of melanomas showed chromosomal aberrations, the benign nevi mostly did not show aberrations. Whereas congenital nevi (Bastian et al., in press) and blue nevi (manuscript in preparation) did not show aberrations at all, a subset of Spitz nevi (about 20%) showed an isolated gain of chromosome 11p (Bastian et al., 1999). The remainder of the Spitz nevi also did not show aberrations. Recent studies showed that this gain was because of the presence of mu...

Characterization of candidate gene copy number alterations in the 11q13 region along with BRAF and NRAS mutations in human melanoma

“…It is also possible that the coamplifications are merely a result of genetic instability that increases during tumor progression but do not contribute directly to the phenotypic alterations. 43 The BRAF V600E mutation frequency in our samples was 26%, which is in concordance with other studies 44,45 but the occurrence of this mutation was lower than it has been reported elsewhere. 4,46 We detected two other BRAF mutations that were distinct from the V600E mutation.…”

Correlation Between Histologic Assessment and Fluorescence In Situ Hybridization Using MelanoSITE in Evaluation of Histologically Ambiguous Melanocytic Lesions

“…[6][7][8][9][10][11][12]17,19 This is reassuring regarding the performance of MelanoSITE. We believe that, in this context, abnormal FISH results clinch the diagnosis, and the lesion can be reported as an outright melanoma.…”

“…16 The Abbott Molecular melanoma FISH test was also validated in critical differential diagnoses concerning histologically unequivocal benign and malignant blue nevi, nevoid melanoma, dysplastic nevi, desmoplastic melanoma, lentiginous melanoma, nevi with atypical epithelioid cell component, and Spitz nevi. [6][7][8][9][10][11][12]17,19 Obviously, a FISH test is not needed for histologically unequivocal cases. The only current justification for use of this expensive test in a diagnostic setting is to employ it as a diagnostic adjunct to help classify histologically ambiguous lesions.…”

“…1 In contrast, tumor progression from a nevus to melanoma is associated with chromosomal instability resulting in gains, amplifications, and/or losses of specific chromosomal material, which can be detected by genetic techniques. 2,3 These findings laid the foundation for the development of the first 4-probe fluorescence in situ hybridization (FISH) test for melanoma, currently commercialized by Abbott Molecular (Abbott Park, Illinois). This test was a subject of our recent comprehensive review.…”

“…6 Several proof-of-principle studies showed potential applications of FISH to solve a variety of diagnostic dilemmas in the evaluation of melanocytic tumors, including differentiating blue nevus-like metastasis from blue nevus, mitotically active nevus from nevoid melanoma, and dysplastic nevus from superficial spreading melanoma. [7][8][9][10][11][12] Fluorescence in situ hybridization test abnormalities characteristic of melanoma were identified in lentiginous melanoma supporting this entity as a variant of melanoma.…”