Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53

Abstract

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 ^V600EBRAF mouse model. In mice expressing ^V600EBRAF 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 ^V600EBRAF-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 ^V600EBRAF 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.