Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53

Nature. 2014 Jul 24;511(7510):478-482. doi: 10.1038/nature13298. Epub 2014 Jun 11.

Abstract

Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear. The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event. 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 melanoma. 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 humans. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / radiation effects*
  • DNA Damage / genetics
  • Disease Models, Animal
  • Female
  • Humans
  • Melanocytes / metabolism
  • Melanocytes / pathology
  • Melanocytes / radiation effects
  • Melanoma / etiology
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Melanoma, Cutaneous Malignant
  • Mice
  • Mice, Inbred C57BL
  • Mutagenesis / genetics
  • Mutagenesis / radiation effects*
  • Mutation / genetics
  • Mutation / radiation effects
  • Nevus / etiology
  • Nevus / genetics
  • Nevus / metabolism
  • Nevus / pathology
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Skin Neoplasms / etiology
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Sunburn / complications
  • Sunburn / etiology
  • Sunburn / genetics
  • Sunscreening Agents / pharmacology
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Ultraviolet Rays / adverse effects*

Substances

  • Sunscreening Agents
  • Tumor Suppressor Protein p53
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf