Genetic Regulation of Melanoma Development

Melanoma is the most fatal and malignant form of skin cancer developing from the pigmented cells, called melanocytes, which occur in the skin epidermis. The highly metastatic nature of this cancer gives patients with this disease a poor prognosis unless the cancerous cells are detected early and surgically excised. Approximately 32,000 cases are diagnosed annually in the United States and the disease incidence is increasing at the rate of about 4.3% per year, making it one of the cancers in this country with the fastest rate of increase. According to the American Academy of Dermatology, in the year 2000, an American's lifetime risk of developing melanoma is 1 in 75 with one person dying of this disease every hour. Approximately 90% of melanomas are seen in patients without any previous family history of the disease and are triggered following excessive exposure to UV rays from the sun. Melanoma cells undergo many chromosomal changes during their evolution that alter the expression of the genes in these regions, thereby leading to the development of this cancer. The chromosomal mechanisms altering gene expression in cancer cells are illustrated in Figure 1. One such non-random alteration occurs in 30-60% of non-familial melanomas and involves genetic lesions of chromosome 10. The genetic change usually entails loss of an entire chromosomal homologue, leading to monosomy, or loss followed by duplication of the remaining chromosome; a condition called uniparental disomy. This process is the second of two hits required to inactivate cancer suppressor genes. Loss of an entire copy of this chromosome could therefore be used to infer the possible "loss-of-function" of multiple cancer suppressor genes on chromosome 10 that regulate melanoma tumor growth. Our recent work has coupled this knowledge of cancer genetics with tumor suppressor gene activity in order to identify and establish a functional role for the genes on chromosome 10 whose loss leads to melanoma tumor development (1, 2, 3). One approach we have developed, that is diagrammatically shown in Figure 2, is called In Vitro Loss of Heterozygosity (IVLOH). It involves transferring a normal copy of chromosome 10 into melanoma cells and then allowing the cells to eliminate segments of the introduced chromosome containing growth suppressing genes (1). These alterations mirror the pattern of chromosome 10 breakage and deletion events that occurs in patient tumors, allows the isolation of many clones from an isogenic background requiring only one chromosome transfer, and leads to the identification of candidate cancer suppressor genes. One of the candidate genes implicated by the IVLOH system was the PTEN phosphatase, which we subsequently confirmed as a melanoma tumor suppressor through mutation analysis and by growth suppression studies in melanoma cells. One of our ongoing projects continues to be to further elucidate the role of the PTEN tumor suppressor in melanoma tumorigenesis. We have also identified a second cancer suppressor on the tip of the short arm of chromosome 10 (10p15.3), and have genetically and functionally tied this gene to melanoma tumorigenesis (2, 3). This cancer suppressor gene causes a significant retardation of tumor growth seemingly due to changes in vascularization, resulting in tumors that were less bloody. We have found that melanoma tumors lacking the 10p15.3 suppressor gene develop interconnecting blood-lakes or channels lined by tumor cells that may play a role in the vascular development of these cancerous masses (3). The formation of these interconnecting channels or lakes can in turn be blocked by introduction of the chromosome 10p15.3 region, accompanied by a significant reduction in tumor growth (2, 3). Similar structures were observed in 45% of metastases obtained from advanced-stage melanoma patients, suggesting a potentially important biological role in tumor development. We are currently elucidating the mechanisms, pathophysiological significance and proteins on 10p15.3 regulating the development of these interconnecting channel-lakes in melanomas. In addition to unraveling the functional role of the genes on chromosome 10, our ultimate objective is establishing a pharmacogenomic understanding of melanoma. To achieve this objective we are creating model tumor systems that will enable us to predict a cells genetic response to particular pharmacological agents. The goal is to provide a means of delivering the best medical treatment for the melanoma patient based on the genetic background of their tumor.