Differential Impact of P16 Mutations with or without Coexpression of MC1R Mutation on the UV Response of Melanocytes and Hence on the Risk for Melanoma
Technical Report,30 Sep 2014,29 Sep 2015
University of Cincinnati Cincinnati United States
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P16 and the melanocortin 1 receptor genes are two important melanoma predisposition genes. We hypothesize that coinheritance of certain germline mutations in p16 and MC1R RHC alleles synergistically sensitizes melanocytes to the damaging effects of UV , and thus increases the chance for malignant transformation to melanoma, by inhibiting autophagy and senescence, and increasing oxidative stress by activating NFB. Our present results using melanocyte cultures from donors heterozygous for a p16 mutation, with or without co-expression of a MC1R non-functional allele, did not differ markedly from melanocytes wild type for p16 and MC1R, or heterozygous for a non-functional MC1R variant in their proliferation capacity, repair of DNA photoproducts, growth arrest, and generation of hydrogen peroxide following a single acute UV exposure. Our results suggest that expression of one functional p16 and MC1R allele is sufficient for maintaining melanocyte homeostasis. We will investigate the response of mutant melanocytes to chronic UV exposure, which might overwhelm their compensatory mechanisms and drive their malignant transformation. These studies are particularly relevant to military personnel with family history of melanoma or a prior melanoma, who are deployed in areas with excessive sun exposure, and should improve melanoma risk assessment based on p16 and MC1R genotypes.