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Melanoma risk in patients with melaoncortin-1 receptor independent of ultraviolet radiation: Is there a way not to be burned by your genome?


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By Warren R. Heymann, MD
July 18, 2016


I admit that my concept of Type I skin red-headed patients getting melanoma was simple: They have a polymorphism(s) of the melanocortin-1 receptor (MC1R), pheomelanin, ultraviolet exposure, DNA damage, increased reactive oxygen species, and voila: melanoma! While conceptually elegant, this is apparently only a partial truth.

Wendt et al compared 991 patient with melanoma to 800 controls, and found that compared with wild-type carriers, those with MC1R variants were at a statistically higher risk (twofold) for melanoma after adjusting for previous ultraviolet exposure (prior sunburns and signs of actinic damage), age, and gender. Although the mechanism(s) behind this striking finding are speculative, the authors note that MC1R variants have been shown to modulate immune functions and inflammation. Importantly, this study confirmed that patients who experienced 10 or more sunburns before the age of 20 years, and those with signs of actinic damage in exposed sites also had an increased risk of melanoma. (1)

I was astounded by this study. Certainly, we are going to continue to advise our patients to do the sun avoidance routing (shade seeking, avoiding the midday sun, sunscreen, etc.), but could there be a way to tweak the genetics of the MC1R polymorphism?

For anyone not interested in following my fanciful theory, this would be a good place to stop.

Understanding the function of genes has increasingly focused on epigenetics — the modification of gene expression, rather than an alteration of the DNA itself. According to Yong et al: “DNA methylation is an epigenetic modification that plays an important role in regulating gene expression and therefore a broad range of biological processes and diseases. DNA methylation is tissue-specific, dynamic, sequence-context-dependent and trans-generationally heritable, and these complex patterns of methylation highlight the significance of profiling DNA methylation to answer biological questions.” (2)

The following is an abstract considering the role of epigenetics in melanoma (3):

The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs. The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes. Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system. Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.

Although there has been an ongoing controversy regarding the utility of folic acid supplementation in reducing cancer risk, the latest data suggests that it has no significant effect on the total cancer incidence (colorectal, prostate, lung, breast, or hematologic), but it reduces the risk of melanoma (3)[in this study].

Folic acid and B12, along with other B complex vitamins, are know to affect epigenetic processes, including DNA methylation in early development. Interestingly, long-term supplementation of folic and B12 may have a similar epigenetic effect in the elderly (4).

Can we prevent our genes from “burning” us and reducing our risk of melanoma with dietary supplementation of folate? That remains to be determined. But it’s hard to argue with any mother who encourages their children to eat their vegetables!

1. Wendt J, et al. Human determinants and the role of melanocortin-1 receptor variants in melanoma risk independent of UV radiation exposure. JAMA Dermatology 2016; 152: 776-782.
2. Yong WS, et al. Profiling DNA genome-wide methylation. Epigenetics Chromatin 2016 June 29; 9:26.
3. Qin X, et al. Folic acid supplementation and cancer risk: a meta-analysis of randomized controlled trials. Int J Cancer 2013; 133:1033-41.
4. Kok DE, et al. The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide methylation in elderly subjects. Clin Epigenetics 2015; 14:7:121.


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