Human malignant melanoma. A genetic disease?

Abstract

Background. Human hereditary malignant melanoma, comprising 5% of all cases of malignant melanoma, occurs in association with other malignancies, predominantly in families with dysplastic nevus syndrome. Additionally, higher incidences of malignant melanoma have been reported in individuals with genetic disorders such as ataxia telangiectasia and xeroderma 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 with the authors' own experimental and clinical experience. Results. Numerous chromosomal regions, as on chromosomes 1 and 9, were altered. The long arm of chromosome 6 was affected in 60% of melanomas. Introduction of a normal copy of chromosome 6 resulted in loss of tumorigenicity in vitro. True melanoma genes were evident in two animal models: the Sinclair swine and the teleost fish Xiphophorus. In the Xiphophorus system, the crossing‐conditioned elimination of a tumor suppressor gene led to the uncontrolled activity of a dominantly acting oncogene in certain hybrids. The causative oncogene, Xmrk, encodes a receptor tyrosine kinase closely related to human epidermal growth factor receptor (EGFR). Among the numerous studied human oncogenes, mutations in the extensively investigated ras family are the result rather than the cause of malignant transformation. High expression of nuclear oncogenes simply may be a common feature of rapidly dividing cells. The receptor tyrosine kinase EGFR may be involved in late stage melanoma; the human exon with homology to Xmrk shows elevated transcription levels in 80% of human melanoma metastases. Deletions of the tumor suppressor gene MTS 1 may be important for melanoma formation, whereas deletions of p53 appear to be of minor relevance. Conclusion. Scientific progress in treating and diagnosing malignant melanoma will largely depend on experimental approaches to define relevant genetic changes by functional analysis rather than descriptive phenomenology and correlative observations. Cancer 1995;75:1228‐37.

Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma

“…Cytogenetic studies have con®rmed the presence of recurring chromosomal alterations which pinpoint the locations of growth regulating genes that may be involved in the progression of human malignant melanoma (Trent et al, 1989;Fountain et al, 1990;Thompson et al, 1995;Kraehn et al, 1995). Chromosome alterations in malignant melanoma most frequently include a variety of nonreciprocal translocations and simple deletions involving chromosome 1 (Trent et al, 1989;Fountain et al, 1990;Thompson et al, 1995), complete or partial loss of the long arm of chromosome 6 (Trent et al, 1989;Fountain et al, 1990) frequent alterations of the short arm of chromosome 9 (Skolnick et al, 1994;Thompson et al, 1995;Kraehn et al, 1995) and 1p11-q22 (Thompson et al, 1995;Kraehn et al, 1995).…”

“…Cytogenetic studies have con®rmed the presence of recurring chromosomal alterations which pinpoint the locations of growth regulating genes that may be involved in the progression of human malignant melanoma (Trent et al, 1989;Fountain et al, 1990;Thompson et al, 1995;Kraehn et al, 1995). Chromosome alterations in malignant melanoma most frequently include a variety of nonreciprocal translocations and simple deletions involving chromosome 1 (Trent et al, 1989;Fountain et al, 1990;Thompson et al, 1995), complete or partial loss of the long arm of chromosome 6 (Trent et al, 1989;Fountain et al, 1990) frequent alterations of the short arm of chromosome 9 (Skolnick et al, 1994;Thompson et al, 1995;Kraehn et al, 1995) and 1p11-q22 (Thompson et al, 1995;Kraehn et al, 1995). Evidence of a putative tumor suppressor gene on chromosome 6 has been suggested by cytogenetic observation (Trent et al, 1989;Fountain et al, 1990), by high frequency of loss of heterozygosity (LOH) along 6q (Milliken et al, 1991;Walker et al, 1994) and by studies suggesting that either tumorigenicity or metastasis of melanoma cell lines can be suppressed by the introduction (following micro-cell mediated chromosome transfer) of a normal copy of human chromosome 6 (Trent et al, 1990;You et al, 1995;Ray et al, 1996).…”

Use of Gene Expression and Pathway Signatures to Characterize the Complexity of Human Melanoma

“…Consistent with these results, epidermal growth factor receptor expression has been shown in metastatic melanoma. 33 Interestingly, one study 34 has shown clinical activity of tamoxifen in metastatic melanoma, with dacarbazine plus tamoxifen treatment resulting in improved response rates and survival compared with dacarbazine treatment alone among women. The M1 subset also exhibits elevated …”

Genética molecular aplicada ao câncer cutâneo não melanoma

“…The involvement of some oncogenes and tumor suppressor genes in the development of cancers and related syndromes, such as melanoma, 21,22 CBC, 23 neuroblastoma, 24 cancer of the pancreas, 25 of the ovary, 26,27 non polyposis colon cancer, 28 BCNS, 29 retinoblastoma, 30 Li-Fraumeni syndrome, 31 multiple sporadic cancers, 32 among others, are represented in charts 2 and 3.…”