09 October 2015

EADV Congress - Always the Sun? Other Factors might Increase the Risk of Melanoma

Copenhagen, 9 October 2015. UV is the most prominent risk factor associated with melanoma. About 65% of melanomas worldwide can be attributed to UVR exposure – but what about the other 35%? Development of melanoma skin cancer is multifactorial and there are countless biological, cultural and geographical factors beyond our control that operate, as Prof. Veronique del Marmol, MD (Brussels, Belgium), pointed out at the EADV press conference in Copenhagen today.

So what do the shadows conceal? In order to define the risk factors related to the non UV induced melanoma, we need to clarify what is non UV related melanoma and what are its possible associated risk factors. Using the WHO definition, a risk factor is any attribute, characteristic or exposure of an individual that increases the likelihood of developing a disease or injury. One can consider risk factors as intrinsic or extrinsic.

Intrinsic Risk Factor: Somatic and germinal mutation
About 10% of all melanomas have a familial origin related to a germline mutation (which is inheritable due to its presence in egg or sperm), rather than a somatic mutation (which is non-inheritable and acquired during one’s lifetime). Before 2011, only two major germline mutations (CDNK2 and CD4) corresponding to 40% of all familial origins had been defined. Since then, new genomic sequencing technologies have allowed more germline mutations to be identified. Each of these mutations accounts for less than 1% of all familial clustering of melanoma (BAP1, TERT, MITF, ACD, POT1 and TERF221P), which means than about half of all melanoma-prone families have yet to be identified.

Different pathways that normally play a role in cellular growth and survival have recently been identified. Mutations in pathways (e.g. BRAF, NRAS, MITF) can cause cancer. Therefore, the identification of pathways and typical mutations can provide an opportunity to develop targeted therapies and have already changed the therapeutic landscape. But the mechanisms by which these mutations occur are still unknown.

Epigenetic Modifications by Extrinsic Risk Factors
Overexpression of non-coding RNA (Mir-21) is a common molecular feature of malignant melanoma.  Mir-21 can interact with gene expression and plays a crucial role in regulatory circuits involving epigenetic switches required for the transformation of cancer cells. Therefore, these epigenetic modifications provide a link to risk factors that are environmental or lifestyle-related. Not only UV irradiation, but also noxious chemicals, air pollution, smoking, chronic inflammation, Western nutrition, obesity and sedentary lifestyles might cause an overexpression of miR-21 and are therefore proposed to be risk factors of malignant melanoma1. Even cow milk has been discussed to be a risk factor, because bovine miR-21, a predominant miR constituent of cow’s milk, is identical to human miR-21.

Another risk factor that has lately been discussed is the use of the impotence drug Sidenafil, a PDE5A inhibitor. It is possible that medications that down-regulate the PDE5A pathway may promote melanoma formation. It was shown that sildenafil users had a significantly elevated risk of invasive melanoma (multivariate-adjusted HR (95% CI) of 2.24 (1.05–4.78))2.

“Even if non-UV related melanomas are rare, we have to be aware of them. They are frequently fatal because of a late diagnosis (less visibility, like mucosal melanoma) and because there are fewer therapy options for these particular disease subtypes”, explains Prof. del Marmol. “And we have to be conscious that other risks factors such as lifestyle factors - medications or pollutants - may play a role in the development of these malignancies.”

(1) Melnik BC. MiR-21: an environmental driver of malignant melanoma? J Transl Med 2015; 27; 13: 202
(2) Li WQ et al. Sildenafil use and increased risk of incident melanoma in US men: a prospective cohort study. JAMA 2014; 174(6): 964-970

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