Melanoma genetics and cytogenetics

Abstract

It is now well established that cancer has a genetic basis and is accompanied by structural alterations in the chromosomal DNA. Often, these alterations occur in genes playing an important role in the regulation of proliferation and differentiation. The function of these genes is directly related to the process of oncogenic transformation, and therefore these genes are often referred to as oncogenes. 1 Apart from the biochemical and molecular evidence for altered genes in cancer cells, also cytogenetic and classical genetic studies hint at genetic defects that correlate with the development of cancer; in virtually all cancer cells chromosomal defects can be discerned and in a number of human cancer types hereditary defects determining the disease do occur. Often, the inheritance is determined by inactivation of one allele in one of the genes involved in the suppression of cancerous properties, the so-called tumor suppressor genes. 2 In that case cancer becomes manifest when the remaining intact allele of the gene is inactivated by a somatic mutation. A serious complication in establishing the genetic defect in hereditary cancer is that the development of cancer is a multistep process involving more than one gene. 3 So far, no consistent combinations of gene defects have been found in almost any form of human cancer, which makes it difficult to ascertain one particular gene defect that is associated with transmission of the disease. In cutaneous melanoma, about 10% of the cases are familial, and in such cases melanoma is usually associated with an inherited cutaneous phenotype, the familial atypical multiplemole melanoma (FAMMM) syndrome, also called familial dysplastic nevus syndrome (see the article by Bergman and Fusaro in this issue). The atypical nevi can be considered as precursor lesions for melanoma; therefore, the development of melanoma, at least in FAMMM patients, is likely to take place in at least two distinct steps, one leading to atypical melanocytes and the subsequent step correlated with the transition to melanoma. As about half of the patients with sporadic melanoma have atypical moles as compared with only 2 to 9% of the overall population, it seems that sporadic melanoma and familial melanoma have similar genetic defects determining the precursor stage. Also with respect to clinical and histologic features, no differences have been found, indicating that the subsequent genetic alterations leading to melanoma are similar in sporadic melanoma and the FAMMM syndrome. In this article, I briefly exemplify the hereditary features of melanoma and summarize the genetic and cytogenetic defects associated with the FAMMM syndrome and cutaneous melanoma. Furthermore, I review the alterations in tumor suppressor genes and oncogenes in melanoma and discuss their possible role in the various evolutionary steps of this tumor.