UV Radiation Drives Melanoma by Inducing TP53 Mutations

Epidemiologic studies have established a link between exposure to UV radiation and cutaneous melanoma, but although UV radiation is known to induce DNA damage, the molecular mechanisms by which UV exposure promotes melanomagenesis remain unclear. Viros and colleagues expressed BRAF^V600E in the melanocytes of adolescent mice and found that a single dose of UV radiation equivalent to what would cause mild sunburn in humans induced melanocyte proliferation and nevi formation. Whereas BRAF^V600E expression alone led to tumor formation in approximately 70% of mice with a median latency of just over 1 year, 100% of BRAF^V600E-expressing mice repeatedly exposed to UV radiation developed melanoma at a median latency of only 5.3 months. Of note, application of sunscreen significantly delayed the onset of UV-driven melanoma in BRAF^V600E mice, but all mice still developed tumors at a median latency of 7.5 months, providing preclinical evidence that sunscreen can confer partial protection against UV-induced melanoma in susceptible individuals. Whole-exome sequencing revealed a significant increase in single-nucleotide variants in UV-induced tumors compared with unexposed tumors and identified mutations in Trp53 in 40% of tumors, almost all of which were cytosine-to-thymine transitions at the 3′ end of pyrimidine dimers that are indicative of UV-induced DNA damage. Consistent with these findings indicating that Trp53 is a target of UV radiation in melanoma, TP53 mutations were significantly more common in human melanomas with a UV-induced mutational signature. Expression of one mutant allele of Trp53 markedly accelerated melanoma formation in BRAF^V600E mice, with all mice developing tumors within 3.5 months, suggesting that UV-induced Trp53 mutations cooperate with BRAF^V600E. Together, these findings provide evidence that TP53 mutations play a role in melanoma as well as insight into how UV radiation can promote melanomagenesis.

Viros A, Sanchez-Laorden B, Pedersen M, Furney SJ, Rae J, Hogan K, et al. Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53. Nature 2014 Jun 11 [Epub ahead of print].

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