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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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