AI Article Synopsis
- Coinheritance of mutations in the CDKN2A gene and the loss-of-function variant in the MC1R gene increases the risk of developing melanoma.
- Researchers conducted experiments on human melanocyte cultures from individuals with CDKN2A mutations, revealing normal growth and response to UV radiation in most cultures.
- The study suggests that for melanocytes with both CDKN2A mutations and MC1RLOF variants to become cancerous, they need to acquire additional mutations, influenced by their genetic environment or surrounding cell types.
Article Abstract
Coinheritance of germline mutation in cyclin-dependent kinase inhibitor 2A (CDKN2A) and loss-of-function (LOF) melanocortin 1 receptor (MC1R) variants is clinically associated with exaggerated risk for melanoma. To understand the combined impact of these mutations, we established and tested primary human melanocyte cultures from different CDKN2A mutation carriers, expressing either wild-type MC1R or MC1RLOF variant(s). These cultures expressed the CDKN2A product p16 (INK4A) and functional MC1R. Except for 32ins24 mutant melanocytes, the remaining cultures showed no detectable aberrations in proliferation or capacity for replicative senescence. Additionally, the latter cultures responded normally to ultraviolet radiation (UV) by cell cycle arrest, JNK, p38, and p53 activation, hydrogen peroxide generation, and repair of DNA photoproducts. We propose that malignant transformation of melanocytes expressing CDKN2A mutation and MC1RLOF allele(s) requires acquisition of somatic mutations facilitated by MC1R genotype or aberrant microenvironment due to CDKN2A mutation in keratinocytes and fibroblasts.
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| http://dx.doi.org/10.1111/pcmr.12732 | DOI Listing |
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