Melanoma, UV radiation, and TP53

CIMG1255It’s summer, and time to get some tan. Many people flock to beaches and parks and expose as much skin as possible, bathing in sunlight – and ultraviolet (UV) radiation. Over the past decades, public health campaigns have rather successfully taught people that too much sun, UV radiations, and resulting sunburn is dangerous, as it increases the risk of skin cancer. We now know that we should limit exposure, use sunscreen and/or protective clothing.

Melanoma is the most serious type of skin cancer. It develops in the melanocytes, the skin cells that produce melanin and give the skin its color. Although epidemiological data have linked melanoma and UV radiation, the molecular mechanisms underlying this link remain unclear. In a study published in Nature in July, researchers have looked at the effect of UV radiation on the development of melanoma in a mouse model and identified the tumor suppressor gene TP53 as a target of UV-induced mutations contributing to melanoma development.

A single substitution mutation in the BRAF gene, called BRAF(V600E), is the most common genetic mutation found in melanoma cells and is known to be an early event in the development of melanoma. Researchers therefore used adolescent mice genetically modified to express the BRAF(V600E) mutation in melanocytes and exposed some of them to low levels of UV radiation, mimicking mild sunburn in humans.

Melanoma developed in about 70% of the mice that had not been exposed to UV radiation (55 mice in total), with a median latency of about 13 months, ranging from about 1 to 24 months. By contrast, all mice that had been exposed to UV radiation (19 mice) developed melanoma, with a median latency of about 5 months, ranging from about 3 to 7 months. As the level of UV radiation exposure used in this experiment did not induce melanoma in mice without the BRAF(V600E) mutation (14 mice in this group), researchers concluded that exposure to UV radiation accelerated the development of melanoma initially driven by the BRAF(V600E) mutation.

Application of sunscreen (UVA superior, UVB SPF 50) thirty minutes before exposure to UV radiation did not prevent but only delayed the acceleration of BRAF(V600E)-driven melanoma development, as all mice in this group (22 mice) ended up developing melanoma after a median of 7.5 months, ranging from about 4 to 17 months. (The delay in melanoma development observed in the sunscreen-receiving group compared to the non-sunscreen receiving group was large enough to be statistically significant though).

Trying to understand how UV radiation accelerated the development of BRAF(V600E)-driven melanoma, the researchers analyzed the DNA damage induced by UV radiation and especially focused on the tumor suppressor gene Trp53. They found mutations in this gene in 40% of the UV radiation-exposed melanoma tumors, but in none of the non-UV radiation-exposed tumors. Mice genetically modified to express a mutant Trp53 (one of the mutations that had been identified in the UV radiation-exposed melanoma) in their melanocytes did not develop melanoma. However, when the researchers next crossed them to BRAF(V600E) mice, they observed that the resulting offspring (that expressed both Trp53 and BRAF mutations) developed melanoma tumors within 3.5 months, suggesting that mutations in the Trp53 gene is one of the mechanisms underlying UV radiation-induced acceleration of BRAF(V600E)-driven melanoma.

The researchers also found that about 20% of human melanomas carry mutations in the TP53 gene (human gene corresponding to mouse Trp53, it is also called p53) and that these are associated with UV radiation-induced DNA damage, indicating that the data obtained in the mouse model may be relevant to what happens in a proportion of human melanomas.

TP53 is known to be involved in other non-melanoma skin cancers linked to UV radiation exposure, and this study now suggests that it may also be implicated in the development of melanoma associated with UV radiation. Further studies will be needed to understand how mutant forms of TP53 contribute to promote melanoma development at the molecular and cellular level.

Side note:
Many news outlets that reported on this study did so with headlines that read something like “Study concludes that sunscreen does not protect against skin cancer”. I think this is going pretty far for a study whose primary aim was not to look at the efficacy of sunscreen (and certainly not in humans), that focused on one type of skin cancer (melanoma), and that used mice expressing a genetic mutation that induces melanoma development even without UV radiation exposure. That being said, the experiment anyway showed that use of sunscreen did delay the acceleration of melanoma development following exposure to UV radiation, and the researchers even state, as the last sentence of their study abstract : “Our study validates public health campaigns that promote sunscreen protection for individuals at risk of melanoma.
In any case, writing something as general as “sunscreen does not protect against skin cancer” in a headline seems rather irresponsible to me, when it is established that sunscreen does help protect against other types of skin cancer, regardless of how much it can help in the case of melanoma.

Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53. Viros A, Sanchez-Laorden B, Pedersen M, Furney SJ, Rae J, Hogan K, Ejiama S, Girotti MR, Cook M, Dhomen N, Marais R. Nature. 2014 Jul 24;511(7510):478-82. doi: 10.1038/nature13298
PMID: 24919155

ResearchBlogging.orgViros A, Sanchez-Laorden B, Pedersen M, Furney SJ, Rae J, Hogan K, Ejiama S, Girotti MR, Cook M, Dhomen N, & Marais R (2014). Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53. Nature, 511 (7510), 478-82 PMID: 24919155


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