Critical Wavelength®
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Education is the key 
                        to protection!

Melanoma and Sun Exposure
Karl Gruber M.D.

 

Although melanoma incidence and deaths continue to increase in most populations,[1] [2]  uncertainty persists as to precisely which wavelengths of light cause melanoma and the exact mechanisms of action involved in melanoma induction. 

However there is abundant, largely overlooked, evidence linking short and long wavelength UVA rays to melanoma. This evidence includes both animal models and epidemiological evidence. This is a vital public health issue, particularly as sunscreens are currently only rated for UVB protection (SPF system) and consumers are confused about the different health issues posed by UVB and  UVA exposure.

 

WHAT IS KNOWN ABOUT MELANOMA

There is significant epidemiological and genetic evidence showing that UVA exposure is the cause of sun induced  melanoma[3] [4] [5] [6], whereas other skin cancers (squamous cell and basal cell carcinomas) are largely a UVB phenomenon.

High energy UVB rays are able to produce direct DNA damage. They produce “signature mutations” such as pyrimidine dimers and 6-4 photoproducts. These characteristic UVB fingerprints are seen commonly in non-melanoma skin cancers (squamous cell and basal cell carcinoma) but are not seen in melanomas. Further; BRAF mutations, common in melanomas occurring on sun exposed areas,[7] [8] [9] are not seen in melanomas occurring on sun protected sites.[10] [11] [12] In fact, about 90% of BRAF mutations occurring in sun exposed melanomas involve a single nucleotide substitution -T1799A[13] [14], a mutation not cause by UVB rays, (pyrimidine dimers or photoproducts), but oxidative damage secondary to UVA exposure.[15] [16]

 

How does UVA exposure cause the damage necessary for development of melanoma?

Given that environmental sunlight is a mix of different wavelengths, and of different strengths,  the study of human subjects to determine a mechanism of action for development of melanoma is problematic to say the least. One has been left to the study of animal models. One of the best of these is the fish Xiphophorus model. In this fascinating study by Dr. Richard Setlow, there were melanoma induction peaks in not only the long wavelength UVA I region, but even extending into the visible light range.  It was not until recently that scientist understood  the true damage posed by UVA rays, particularly long wavelength UVA I rays.  

Part of this confusion arose from  studies of albino mice in which UVA exposure does not cause melanoma induction. However we now know that melanin is the key sensitizing chromophore in melanocytes.  The interaction of UVA light, together with melanin granule containing melanocytes; are necessary to initiate the process of turning a melanocyte into melanoma. Albino mice developed pyrimidine dimer melanomas, not BRAF positive tumors. 

Some of the best evidence for the necessity of melanin granules involves epidemiologic observations of sun damage in albino African-Americans and versus non-albino African-Americans. African-Americans rarely develop sun induced melanomas (or other skin cancers)[17]. Melanin granules produced by melanocytes are transported out of the cells and deposited within the epidermis. This not only makes African-Americans dark, but melanin provides a protective effect, keeping UVA from rays penetrating beyond the epidermis. However, albino African-Americans who do not produce melanin granules quickly develop skin cancers (basal cell and squamous cell carcinomas), but they do not develop melanomas. They have lost the protective effect of melanin deposition in the epidermis (thereby developing basal cell and squamous cell carcinomas). However, without melanin granules they do not develop  melanoma (BRAF positive).

 

Melanin as a photosesitizer

Illumination of melanin by UVA rays, generates reactive melanin radicals (RMR) that react with oxygen to produce oxidants such as superoxide, which ultimately results in the formation of hydrogen peroxide and hydroxyl radicals. In the fish Xiphophorus model, these melanin sensitized free radicals are the central key event causing melanoma. Further work has shown the ability of UVA light to produce these RMR’s  extends way into the long wavelength UVA region and into the visible light range, the region in which most sunscreens either provide little or no protection[18][19].

Hv + RMR → O2 + H2O2 + HO  → Cell Damage  →  Melanoma mutation → Melanoma

It is further hypothesized that a certain UV threshold is necessary to deplete a melanocytes of  antioxidant defenses. This may account for the strong association of melanoma with episodes of acute sunburn producing UV exposure.

 

Take home points

If the above hypothesis is correct, UVA and not UVB rays are the main cause of melanoma. This brings up a couple of issues:

  1. The total flux or amount of UVA rays at the earth surface vastly exceeds that of UVB rays. UVA and longer wavelength rays remain relatively constant throughout the day and throughout the year, unlike UVB rays.
  1. Most sunscreens do not provide adequate protect against UVA/melanoma. There is little that is as controversial as this statement, but sunscreens were designed to protect against UVB induced sunburns, and the SPF system only rates the level of UVB protection. Further, poorly designed sunscreens with high UVB, but low UVA protection may actually facilitate longer exposure to UVA inducing melanoma rays.
  1. Seek out products with a UVA rating. Consumers looking for high levels of UVA protection need to look for products with a UVA rating. PPD or persistent pigment darkening has been used in Japan and Europe for years and is the basis for the PA rating of + to +++. Unfortunately, PFA does not provide information about long wavelength UVA protection.

 

Critical Wavelength® by contrast, is a good in-vitro test that is an accurate measure of both long and short wavelength UVA protection (for sunscreens with a SPF 15 and higher).  The  American Academy of Dermatology recommends that consumers look for products with a critical wavelength of 370nm or higher. The AAD is actually urging that an absolute critical wavelength value be placed on every bottle of sunscreen- it is that important.


Acknowledgments

The author would like to thank Leslie P. Lund and Graham S. Timmons for their excellent review of melanoma and long wavelength UV light[20].  It incorporates the best data from the last two decades for a compelling argument about the dangers of UVA exposure.


[1] Longstreet, J. (1988). Cutaneous malignant melanoma and ultraviolet radiation: a review. Cancer Metastasis Rev 7, 321-333.

[2] Woodhead, A.D., Setlow, R.B., & Tanaka, M. (1999). Environmental factors in nonmelanoma and melanoma skin cancer. J Epidemiol 9, S102-S114

[3] Moan, j., Dahlback, A., & Setlow, R.B. (1999), Epidemiological support for a hypothesis for melanoma induction indicating a role for UVA radiation. Photochem Photobiol 70, 243-247.

[4] Oliveria, S., Dudek, J., & Berwick, M. (2001). Issues in the epidemiology of melanoma. Expert Rev Anticancer Ther. 453-459.

[5] Wang, S., Setlow, R,. Berwick, M,. Polsky, D., Marghoob, A., kopf, A., et al. (2001). Ultraviolet A and melanoma: a review, J Am Acad Dermatology 44, 837-846.

[6] Garland, C., Garland, F., & Gorham, E. (2003) Epidemiologic evidence for different roles of ultraviolet A and B radiation in melanoma mortality rates. . Ann  Epidemiol 13, 395-404.

[7] Gordon, A,. Osman, I., Gai, W., He, D., Huang, W., Davidson, A., et al. (2003). Analysis of BRAF and N-RAS  mutations in metastatic melanoma tissues. Cancer Res, 1276-1286.

[8] Pollock, P.M., Harper, U.L., Hansen, K.S., Yudt, L. M., Stark, M., Robbins, C. M., et al. (2003). High frequency of BRAF mutations in nevi. Nat Genet 33, 19-20.

[9] Goldenberg-Cohen, N., Cohen, Y., Rosenbaum, E., Herscovici, Z., Chowers, I., Weinberger, D., et al. (2005)T1799A BRAF mutations in conjunctival melanocytic lesions. Invest Ophthalmol Visual Sci 46, 3027-3030.

[10] Edwards, R., War, M., Wu, H., Medina, C., Brose, M., P.V., et al. (2004). Absence of BRAF mutations in UV protected mucosal melanomas. J Med Gen 41, 270-272.

[11] Helmke, B.M., Mollerhauer, J., Herold_Mende, C., Benner, A., Thome, M., Gassler, N., et al. (2004). BRAF mutations distinguish anorectal from cutaneous melanoma at the molecular level. Gastroenterology 127, 1815-1820.

[12]Wong, C., Fan, Y., Chan, T., Chan, A.,  Ho, L., Ma, T., et al. (2005). BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs, J. Clin Pathol 58, 640-644.

[13]Brose, M. S., Volpe, P., Feldman, M., Kumar, M., Rishi, I., Gerrero, R., et al. (2002). BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62, 6997-7000.

[14]Davis, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., et al (2002). Mutations of the BRAF gene in human cancer. Nature 417, 949-954.

[15] Edwards, R., War, M., Wu, H., Medina, C., Brose, M., P.V., et al. (2004). Absence of BRAF mutations in UV protected mucosal melanomas. J Med Gen 41, 270-272.

[16] Ragnarsson-Olding, B.K., Karsberg, S., Platz, A., & Ringborg, U.K. (2002). Mutations in the TP53 gene in human malignant melanomas derived from sun-exposed skin and unexposed mucosal membranes. Melanoma Res 12, 453-463.

[17] Moan, j., Dahlback, A., & Setlow, R.B. (1999), Epidemiological support for a hypothesis for melanoma induction indicating a role for UVA radiation. Photochem Photobiol 70, 243-247.

[18] Setlow, R.B., (1999). Spectral regions contributing to melanoma: a personal view. J Investig Dermatology Symp Proc 4, 46-49.

[19] Setlow, R. B., & Woodhead, A. D., (1994). Temporal Changes in the Incidence of Malignant-Melanoma: explanation from Action Spectra. Mutat Res 307, 365-374.                   

[20] Lund, L. & Graham,, T. (2007). Melanoma, long wavelength ultraviolet and sunscreens: Controversies and potential resolutions. Pharmacy & Therapeutics 114, 198-207.

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