Melanocortin 1 receptor (MC1R) is a G protein-coupled receptor expressed on the surface of melanocytes that signals to downstream effectors, such as the microphthalmia-associated transcription factor, to regulate skin pigmentation and to control cell proliferation and apoptosis1. Melanin is generated by melanocytes in two major forms, pheomelanin and eumelanin. Unlike eumelanin, which is dark brown or black in colour, pheomelanin is red/orange, and is associated with type I/II skin, freckles, red hair and an inability to tan2. People with this phenotype are generally highly photosensitive, and prone to sunburn when exposed to ultraviolet (UV) light3.
Population sequencing studies have revealed a number of null or hypomorphic MC1R alleles, which are collectively referred to as R alleles and are strongly associated with the red hair and light skin phenotype4,5. Other missense variants are referred to as r alleles and are less strongly associated with this hair colour and complexion4,6. While R/R individuals are generally red heads, and persons with 0 or 1 R alleles are rarely red heads, pigmentation traits such as degree of tanning after repeated UV exposure3 and skin reflectance7 depend additively on the number of R alleles. In addition to regulating skin pigmentation, MC1R signalling has been reported to increase phosphorylation of DNA repair proteins, initiating the DNA damage repair process, and also to activate survival pathways8,9,10,11. As such, polymorphisms in MC1R have been linked to increased melanocyte apoptosis and inefficient DNA repair12. Collectively these factors link MC1R variants to increased melanoma risk6,13,14. In animal model systems, null alleles of Mc1r (Mc1re/e) have been shown to co-operate with BrafV600E to promote melanoma development via mechanisms including enhanced lipid peroxidation, a phenotype rescued on an albino mouse background owing to a lack of pheomelanin production15. This has led to the suggestion that loss of MC1R function, even in the absence of UV light, may be oncogenic. Despite these insights, it is still unclear whether MC1R germline variant alleles influence the genome-wide somatic mutation burden in melanoma.
In this study, we set out to establish the contribution of germline MC1R alleles to the somatic mutation landscape of sporadic melanoma. Mutations found in melanomas are predominantly C>T transitions due to the production of cyclobutane pyrimidine dimers (CPDs) in response to solar UV damage, but other mutational classes such as C>A transversions have also been observed16,17,18,19,20. Indeed, hotspot mutations in key driver genes, such as BRAF and KIT, are almost exclusively acquired as non-C>T mutations17. Our results indicate that individuals with one or two germline MC1R R alleles have a significantly higher somatic mutational load than individuals with no R alleles. This finding has implications for our understanding of melanomagenesis, as well as the identification of individuals at higher risk of developing melanoma.
https://www.nature.com/articles/ncomms12064
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