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  1. Melanoma is one of the more common cancers in the United States and has increased rapidly in occurrence. Environmental factors, particularly sun exposure, have been strongly implicated in melanoma risk. However, phenotypic differences in pigmentation between individuals are also of paramount importance in assessing risk. Recent advances in the study of vertebrate pigmentation show that there is still room for further study and additional discovery of genes implicated in skin tone and melanoma susceptibility.

  2. The role of ultraviolet (UV) radiation remains controversial. UV radiation may mutate key genetic targets directly or, alternatively, may function by suppressing the immune response and by inducing growth factors in the microenvironment in which melanocytes reside.

  3. An accumulation of evidence points to a set of genetic changes that underlie the evolution from melanocyte to metastatic melanoma. This transition can be modeled experimentally. Several permutations of such experimental models that include important microenvironmental interactions are presented, and the features of such models are discussed briefly.

  4. A fraction of melanoma cases is familial, and nearly all advanced melanomas show additional somatic genetic abnormalities. Among the inherited loci, the 9p21 genomic region harbors two proven tumor-suppressor proteins encoded by CDKN2A, p16, and p14 ARF that are involved in melanoma susceptibility. Identification of additional loci and their contribution to melanoma susceptibility are discussed. Recent studies suggest that more information could be obtained by thorough testing of patient-derived materials.

  5. The investigation of somatic lesions in melanoma tumors and cell lines has permitted clinicians and molecular geneticists to focus on defined regions in the genome. Somatic mutations at the BRAF oncogene are prevalent in the disease. BRAF mutations are implicated in approximately 60 percent of melanomas but are also found in both acquired and congenital nevi. One amino acid change in the BRAF protein (V600E) is by far the most prominent genetic lesion and results in a constitutively active mitogen-activated protein kinase (MAPK) pathway. In experimental systems, expression of BRAF V600E induces malignant transformation in melanocytes in combination with other genetic changes that are necessary for malignant transformation.

  6. Additional loci implicated as being inherited in a mutated form include PTEN, CDK4, and CDK6, albeit in lower percentages. Oncogenes such as those of the RAS gene family also have been found to be mutated somatically, but their mutational spectrum differs from that observed in other well-studied neoplasms. Several other loci, such as NOTCH, KIT, MITF, WNT5a, and NEDD9, are also implicated in studies of melanoma progression.

  7. The identification of inherited and somatic mutations involved in melanoma raises the possibility of gene-based tests for cancer risk. Additionally, molecular genetic classification of tumors is currently being performed, often simultaneously with more traditional histochemical and anatomic classification, during treatment. It is hoped that precise knowledge of underlying melanoma genetics will lead to specific therapies suited to each patient.

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