Abstract
To investigate whether pigmentation genes involved in the melanogenic pathway (melanogenesis) contributed to melanoma predisposition, we compared pigmentary genetics with quantitative skin pigmentation measurements, the number of atypical nevi, the total nevus count, and the familial atypical multiple mole and melanoma (FAMMM) syndrome. We typed 32 pigmentary SNP markers and sequenced MC1R in 246 healthy individuals and 116 individuals attending periodic control for malignant melanoma development, 50 of which were diagnosed with FAMMM. It was observed that individuals with any two grouped MC1R variants (missense, NM_002386:c. 456C > A (p.TYR152*), or NM_002386:c.83_84insA (p.Asn29Glnfs*14) had significantly (p<0.001) lighter skin pigmentation of the upper-inner arm than those with none or one MC1R variant. We did not observe any significant association of the MC1R variants with constitutive pigmentation measured on the buttock area. We hypothesize that the effect of MC1R variants on arm pigmentation is primarily reflecting the inability to tan when subjected to UVR. A gender specific effect on skin pigmentation was also observed, and it was found that the skin pigmentation of females on average were darker than that of males (p<0.01). We conclude that MC1R variants are associated with quantitative skin colour in a lightly pigmented Danish population. We did not observe any association between any pigmentary marker and the FAMMM syndrome. We suggest that the genetics of FAMMM is not related to the genetics of the pigmentary pathway.
Highlights
Human skin colour is greatly influenced by environmental factors, including ultraviolet radiation (UVR)
Vitamin D synthesis requires UVR and human skin colour diversity reflects the balance of letting enough UVR through the skin to produce vitamin D and preventing DNA-damage caused by UVR [2]
DNA damage in the keratinocyte induces expression of tumour protein p53 (P53), which induces melanin synthesis by increasing the level of α-melanocyte stimulating hormone that binds to the melanocytemembrane-bound melanocortin 1 receptor (MC1R) and increases the cAMP level in the melanocytes
Summary
Human skin colour is greatly influenced by environmental factors, including ultraviolet radiation (UVR). Eumelanin is more efficient than pheomelanin in blocking UVR and in scavenging the reactive oxygen species produced from UVR of the skin (reviewed in [4]). DNA damage in the keratinocyte induces expression of tumour protein p53 (P53), which induces melanin synthesis by increasing the level of α-melanocyte stimulating hormone (αMSH) that binds to the melanocytemembrane-bound melanocortin 1 receptor (MC1R) and increases the cAMP level in the melanocytes. This results in increased transcription of several pigmentation genes via microphtalmia associated transcription factor (MITF) (reviewed in [7])
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