HUMAN-MALIGNANT MELANOMA - A GENETIC-DISEASE

Background. Human hereditary malignant melanoma, comprising 5% of all cases of malignant melanoma, occurs in association with other malignan cies, predominantly in families with dysplastic nevus syndrome. Additi onally, higher incidences of malignant melanoma have been reported in individuals with genetic disorders such as ataxia telangiectasia and x eroderma pigmentosum. The results and observations as reported in the literature on the involvement of oncogenes and chromosomal aberrations in the development of malignant melanoma are reviewed and compared wi th the authors' own experimental and clinical experience. Results. Num erous chromosomal regions, as on chromosomes 1 and 9, were altered. Th e long arm of chromosome 6 was affected in 60% of melanomas. Introduct ion of a normal copy of chromosome 6 resulted in loss of tumorigenicit y in vitro. True melanoma genes were evident in two animal models: the Sinclair swine and the teleost fish Xiphophorus. In the Xiphophorus s ystem, the crossing-conditioned elimination of a tumor suppressor gene led to the uncontrolled activity of a dominantly acting oncogene in c ertain hybrids. The causative oncogene, Xmrk, encodes a receptor tyros ine kinase closely related to human epidermal growth factor receptor ( EGFR). Among the numerous studied human oncogenes, mutations in the ex tensively investigated ras family are the result rather than the cause of malignant transformation. High expression of nuclear oncogenes sim ply may be a common feature of rapidly dividing cells. The receptor ty rosine kinase EGFR may be involved in late stage melanoma; the human e xon with homology to Xmrk shows elevated transcription levels in 80% o f human melanoma metastases. Deletions of the tumor suppressor gene MT S I may be important for melanoma formation, whereas deletions of p53 appear to be of minor relevance. Conclusion. Scientific progress in tr eating and diagnosing malignant melanoma will largely depend on experi mental approaches to define relevant genetic changes by functional ana lysis rather than descriptive phenomenology and correlative observatio ns.