Letter | Published:

Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53

Nature volume 511, pages 478482 (24 July 2014) | Download Citation

  • A Corrigendum to this article was published on 21 January 2015


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.

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European Nucleotide Archive

Data deposits

Exome sequence and aCGH data have been deposited in the European Nucleotide Archive under study accession number PRJEB6330.


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This work was supported by Cancer Research UK (C107/A10433; C5759/A12328; A13540; A17240), the Wenner-Gren Foundations, Stockholm, Teggerstiftelsen (M.P.) and a FEBS Long-Term Fellowship (B.S.-L.). We thank G. Ashton for technical assistance and A. Young for helpful discussions. We would like to acknowledge the contribution of the melanoma specimen donors and research groups to The Cancer Genome Atlas.

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Author notes

    • Amaya Viros
    • , Berta Sanchez-Laorden
    • , Malin Pedersen
    •  & Simon J. Furney

    These authors contributed equally to this work.


  1. Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK

    • Amaya Viros
    • , Berta Sanchez-Laorden
    • , Simon J. Furney
    • , Kate Hogan
    • , Sarah Ejiama
    • , Maria Romina Girotti
    • , Martin Cook
    •  & Richard Marais
  2. Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK

    • Malin Pedersen
    • , Joel Rae
    • , Nathalie Dhomen
    •  & Richard Marais
  3. Histopathology, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK

    • Martin Cook


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A.V., B.S.-L. and R.M. designed the study, analysed the data and wrote the paper. M.P. designed and performed experiments and analysed data. S.J.F. designed and performed bioinformatics analysis and analysed data. K.H., J.R., M.R.G., M.C. and N.D. performed experiments. S.E. validated WES SNVs.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Richard Marais.

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