The mc1r gene located on 16p24 which is involved in

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Unformatted text preview: located on 16p24, which is involved in the regulation of melanin production by melanocytes, is a 19 low-risk susceptibility gene. Some polymorphic variants of MC1R cause a switch from eumelanin (brown-black) to pheomelanin (red-yellow) synthesis and are associated with sensitive skin type, poor tanning ability and red hair color. It has been shown that such MC1R variants are also associated with the risk of developing both sporadic and hereditary melanoma and acts as a risk modifier in some melanomaprone families with CDKN2A mutations (78). Some MC1R genetypes thus increased the melanoma penetrance in CDKN2A gene carriers from 18 to 55% in Dutch melanoma families (79). Cooperation of RAS and CDKN2A Indications of cooperation of activation of oncogenic RAS accompanied by inactivation of the CDKN2A locus (INK4A, ARF) mostly comes from melanoma animal models. Transgenic mice that express a mutant form of HRAS specifically in melanocytes using the tyrosinase (tyr) promoter showed melanocytic hyperplasia with intense skin pigmentation, which after treatment with carcinogens progressed into skin melanoma with metastasis formation in lymph nodes and lung (80). Breeding of Tyr::H-RASV12G transgenic mice on an INK4A/ARF-deficient background resulted in the development of highly vascularized but amelanotic melanomas resembling nodular melanoma (81). No metastasis was observed in these mice. Melanoma tumors regressed when HRASV12G expression was removed in an inducible melanoma model. This suggests that RAS signaling is essential for both initiation and maintenance of melanoma (82, 83). In contrast, a transgenic mouse line which expresses the oncogenic form of human NRAS (NRASQ61K) in melanocytes on an INK4A-deficient background developed melanotic melanomas with high penetrance, which acquire a metastatic phenotype, spreading to lymph nodes and other distal sites (e.g., lung and liver), thus mimicking the human condition (84). Moreover, it has also been shown in an animal model that oncogenic NRAS collaborates with deficiency in ARF, to fully transform melanocytes. The role of ARF...
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