Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53

Amaya Viros Usandizaga, Berta Lopez Sanchez-Laorde, Malin Pedersen, Simon Furney, Joel Rae, Kate Hogan, Sarah Ejiama, Romina Girotti, Martin Cook, Nathalie Dhomen, Richard Marais

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear1, 2. The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event3. To investigate how UVR accelerates oncogenic BRAF-driven melanomagenesis, we used a BRAF(V600E) mouse model. In mice expressing BRAF(V600E) 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. Here we show that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma, but only provided partial protection. The UVR-exposed tumours showed increased numbers of single nucleotide variants and we observed mutations (H39Y, S124F, R245C, R270C, C272G) in the Trp53 tumour suppressor in approximately 40% of cases. TP53 is an accepted UVR target in human non-melanoma skin cancer, but is not thought to have a major role in melanoma4. However, we show that, in mice, mutant Trp53 accelerated BRAF(V600E)-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 humans5. Furthermore, we identify TP53/Trp53 as a UVR-target gene that cooperates with BRAF(V600E) 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.
    Original languageEnglish
    Pages (from-to)478-482
    Number of pages4
    JournalNature
    Volume511
    Issue number7510
    DOIs
    Publication statusPublished - 11 Jun 2014

    Keywords

    • Melanoma
    • Cancer genetics

    Fingerprint

    Dive into the research topics of 'Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53'. Together they form a unique fingerprint.

    Cite this