Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53

Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear(1,2). The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event(3). To investigate how UVR accelerates oncogenic BRAF-driven melanomagenesis, we used a (V600E)BRAF mouse model. In mice expressing (V600E)BRAF in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. We show that sunscreen (UVA superior: UVB SPF50) delayed the onset of UVR-driven melanoma, but only provided partial protection. The UVR-exposed tumours presented increased numbers of single nucleotide variants (SNVs) and we observed mutations (H39Y, S124F, R245C, R270C, C272G) in the Trp53 tumour suppressor in ~40% of cases. TP53 is an accepted UVR target in non-melanoma skin cancer, but is not thought to play a major role in melanoma(4). However, we show that mutant Trp53 accelerated (V600E)BRAF-driven melanomagenesis and that TP53 mutations are linked to evidence of UVR-induced DNA damage in human melanoma. Thus, we provide mechanistic insight into epidemiological data linking UVR to acquired naevi in humans(5). We identify TP53/Trp53 as a UVR-target gene that cooperates with (V600E)BRAF to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. Our study validates public health campaigns that promote sunscreen protection for individuals at risk of melanoma.