COPENHAGEN – Sunlight is recognized as the 800-pound gorilla of melanoma risk, with roughly 65% of all melanomas worldwide attributable to exposure to UV radiation. But what about the other 35%?
About 10% of melanomas are due to an inherited germline mutation, and new germline mutations are being discovered all the time. However, the incidence of melanoma has been rising steadily in industrialized countries since the 1950s, and genetic predisposition can’t explain that phenomenon. Environmental and lifestyle factors are likely to be involved. Indeed, melanomas arising from epigenetic modifications by extrinsic environmental and lifestyle factors other than UV exposure are drawing increasing research attention because of the potential for preventing the malignancy through avoidance of these risk factors, Dr. Veronique del Marmol said at the annual congress of the European Academy of Dermatology and Venereology.
Dr. Veronique del Marmol
One promising avenue of investigation focuses on microRNAs (miRs) as environmental drivers of melanoma risk. The miRs are important posttranscriptional regulators of gene expression. In particular, overexpression of miR-21 has been shown to accompany the transition of benign melanocytes into melanoma. miR-21 affects numerous genes critical to oncogenesis, including genes promoting sustained proliferation, angiogenesis, evasion from apoptosis, genetic instability, oxidative stress, and invasion and metastasis, as detailed recently [J Transl Med. 2015 Jun 27;13:202] by Dr. Bodo C. Melnik of the department of dermatology, environmental medicine, and health theory, University of Osnabrück (Germany).
Translational work by Dr. Melnik and others has shown that miR-21 expression is upregulated by several elements that investigators have long suspected are associated with an increased risk of melanoma, including smoking, air pollution, polychlorinated biphenyls and other noxious chemicals, chronic inflammation, a high-fat/high-sugar diet, and a sedentary lifestyle. Even cow’s milk has generated suspicion, since bovine miR-21 is identical to human miR-21, noted Dr. del Marmol, head of the department of dermatology at Erasmus Hospital in Brussels and chair of the pan-European Euromelanoma project.
Two noteworthy factors that have generated interest recently are coffee consumption, shown in a large observational study to protect against melanoma, and sildenafil (Viagra), which was shown in an analysis of 25,848 physicians enrolled in the Health Professionals’ Follow-Up Study to be associated with a 2.24-fold increased risk of subsequently developing melanoma during prospective follow-up (JAMA Intern Med. 2014 Jun;174[6]:964-70).
An association between increased risk of melanoma and the use of sildenafil or other phosphodiesterase-5 (PDE-5) inhibitors commonly used by men with erectile dysfunction is biologically plausible, according to Dr. del Marmol. Activation of oncogenic BRAF is a hallmark of 40%-60% of melanomas, and BRAF activation, like sildenafil use, downregulates phosphodiesterase-5A, which increases the invasiveness of melanoma cells.
The coffee connection was identified through an analysis of food frequency questionnaires completed by 447,357 non-Hispanic whites enrolled in the NIH-AARP Diet and Health Study, a prospective study developed at the National Cancer Institute.
During 4.3 million person-years of follow-up, 2,904 individuals were diagnosed with malignant melanoma. In a multivariate analysis, quaffing 4 or more cups of caffeinated coffee daily was associated with a 25% reduction in the risk of developing melanoma. Lesser consumption had no significant impact on melanoma risk (J Natl Cancer Inst. 2015 Jan 20;107[2]: pii: dju421. doi: 10.1093/jnci/dju421].