UV and melanoma: Genetics, radiation promote pigment

Key Points

Utrecht, The Netherlands - Although sunburns appear to implicate UVB radiation as an etiologic factor, there is still controversy surrounding which ultraviolet wavelengths are most hazardous in relation to melanoma genesis.

It is currently believed that UVB is the most hazardous in terms of developing melanomas in mammals, but results of studies in fish show that UVA can also be significantly harmful and promote the genesis of pigment as well as melanoma.

"We found that intermittent high doses of UVB radiation were effective in inducing nevi, but only few melanomas developed, without mutations in the oncogene B-Raf or N-Ras, which are seen in man. Although the experiments in mammals mostly point at UVB as the most hazardous wavelengths, experiments in Xiphophorus fish show that UVA can be a hazard through radical formation from pigment," says Frank R. de Gruijl, Ph.D., Institute of Dermatology, University Hospital of Utrecht.

However, Dr. de Gruijl found it difficult to produce this mutation with UV in mice. In experiments, ultraviolet was shown to cause such mutations, but never in melanoma.

"N-Ras or B-Raf are genetic triggers and throttles in the process of melanoma genesis. They drive the proliferation, and p16 Ink4a serves as a brake and puts on the brake if there is unauthorized proliferation.

"So, for melanoma genesis, you need the combination of a throttle being pushed and a brake that fails. In melanoma it is apparently a combination of N-Ras or B-Raf with a loss of p16," Dr. de Gruijl tells Dermatology Times.

He says he has not seen N-Ras or B-Raf mutations in nevi or melanomas in his mouse experiments. These mutations are detected in humans, and the aim is to simulate this process in mice.

"One of our goals is to find out whether these mutations are caused by UV or not. In my opinion they are, but this has not yet surfaced in our animal experiments," Dr. de Gruijl says.

Dr. de Gruijl says cancer starts from DNA damage, and mutation and UVB is far more effective in doing that. Melanomas are usually highly pigmented lesions, and Dr. de Gruijl says the issue is that this pigment does not only have protective qualities, but it may also be involved in free radical release, especially in the melanocyte itself.

"We suspect that UVA may be causing melanoma as a result of the release of free radicals in the melanocytes. UVA radiation in fish seems to be only slightly less effective in producing melanoma than UVB. The question is, of course, if this holds true for mammals, because the fish is a rather exotic model," Dr. de Gruijl says.

Dr. de Gruijl says that Yang et al was able to successfully induce melanomas with K-Ras (belonging to the same family as N-Ras in human melanomas) by neonatal UVB exposure of mice, in which the tumor suppressor genes Ink4a/Arf were knocked out.

Therefore, Dr. de Gruijl says experiments in mice have shown that UVB radiation is mainly effective in causing mutations relevant for the development of melanomas, and it is UVB that at sunburning dosages can cause proliferation of melanocytes, which, apparently, promote growth of melanocytic lesions (nevi in hairless mice).

Dr. de Gruijl believes that it is the intermittent UVB or intermittent sunburning that promotes nevi and melanocytic growth. This coincides with epidemiologic studies, where sunburn is seen as a promoting factor of melanoma.

He says intermittent exposure and overexposure drive melanocytic proliferation, and with that, apparently promote melanocytic lesions. It is this intermittency that prevents the skin from aptly adapting to the harmful UV rays.

"Nevertheless, the fish data suggests that neonatal UVA exposure may be effective in initiating melanoma occurring later in life. Mouse models need to be explored further to investigate whether differences in pigmentation, such as more yellow/red pheomelanin instead of the protective, darker eumelanin, may sensitize the melanocyte to gene mutations and transformation into a malignant cell," Dr. de Gruijl says.

There are many emerging animal experiments that simulate the genetic changes that are also seen in human melanoma, and these genetic changes are caused by UVB in these animal models.

Dr. de Gruijl says there are on-going mouse experiments that show the combination of UVA radiation and pigmentation can also be carcinogenic and induce melanoma.

"These animal models provide valuable data, but need to be further developed to emulate and elucidate the role of ultraviolet radiation in melanoma genesis in man," Dr. de Gruijl says.