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

Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53

Amaya Viros #  1 , Berta Sanchez-Laorden #  1 , Malin Pedersen #  2 , Simon J Furney #  1 , Joel Rae  2 , Kate Hogan  1 , Sarah Ejiama  1 , Maria Romina Girotti  1 , Martin Cook  1   3 , Nathalie Dhomen  2 , Richard Marais  1   2
Affiliations

Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53

Amaya Viros et al. Nature. .

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.

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Figures

Figure 1
Figure 1. UV accelerates V600EBRAF-driven naevogenesis
a. Experimental design.. b. Trp53 staining (arrows) in protected and UVR-exposed epidermis 24 hours (24h) after UVR. Bar: 50μm. 5 animals examined. c. Hematoxylin and eosin stained section (H&E) of protected and UVR-exposed epidermis 24h after UVR. Arrows: sunburn cells (apoptotic keratinocytes). Bar: 50μm. d. H&E of protected and UVR-exposed epidermis 7 days (7d) after UVR. Arrows: dermal naevi; double-headed arrows: epidermal/dermal thickness. Bar: 500μm. e. H&E of protected and UVR-exposed epidermis 7 months (7m) after UVR. Arrows: dermal naevi; double-headed arrows: epidermal/dermal thickness. Bar: 500μm. f. Protected and UVR-exposed skin 9 weeks after UVR treatments.
Figure 2
Figure 2. UVR accelerates BRAFV600-driven melanomagenesis
a. Kaplan-Meier showing melanoma-free survival in tamoxifen-treated UVR-exposed CreERT2 mice (CreERT2+UVR; n=14); V600EBRAF mice (V600EBRAF/non UVR; n=55); UVR-exposed V600EBRAF mice (V600EBRAF+UVR; n=19) and UVR-exposed sunscreen-protected V600EBRAF mice (V600EBRAF+UVR+SS; n=22). V600EBRAF/non-UVR vs.V600EBRAF+UVR, p <0.0001;V600EBRAF+UVR vs. V600EBRAF+UVR+SS, p <0.0001; V600EBRAF/non-UVR vs. V600EBRAF+UVR+SS, p= 0.0003; Log-rank Test. All tests are 2-sided. b. Median tumour numbers in V600EBRAF/non-UVR (non-UVR), V600EBRAF+UVR (UVR) and V600EBRAF+UVR+SS (UVR+SS) mice. The error bars show mean ± SD. *** p-<0.0001; ** p-<0.008 Wilcoxon Signed-Rank Test (WSRT). c. Photograph of UVR mouse 5.3 months after UVR and UVR+SS mouse 6.5 months after UVR. Yellow arrows: UVR tumours; white arrow: protected tumours. d. H&E from non-UVR, UVR and UVR+SS mice. Bar: 0.5mm. e. Dashed-boxes from Fig 2d. Black arrows: dermal naevi. Bar: 250μm. f. Solid-boxes from Fig 2d; scale bar 50μm. Inset: black arrows: mitotic cells. Bar: 10μm.
Figure 3
Figure 3. Genome analysis of UVR-driven melanomas
a. Somatic copy number alterations by aCGH in non-UVR and UVR tumours. b. Melanoma oncogene and tumour suppressor gene gains (green) and losses (red) by aCGH in non-UVR and UVR tumours. p=0.0171; WRST. c. Somatic SNVs/Mb in non-UVR (green), UVR (violet) and UVR+SS (orange) tumours; ****: p=1.79e-06; ***: p=1.165e-05; ns: not significant p=0.6461; WRST. d. Proportion of C>T (G>A) transitions at 3′ end of pyrimidine dimers in non-UVR, UVR and UVR+SS tumours. The error bars show the lowest data still within 1.5 IQR of the lowest quartile and highest data within 1.5 IQR of the upper quartile. *** p<0.0001, ** p=0.007698, * p= 0.02558; WRST. e. Proportion of each nucleotide (A: green, C: blue, G: black, T: red) ±1bp of all C to T (G to A) transitions in non-UVR, UVR and UVR+SS tumours.
Figure 4
Figure 4. Mutant Trp53 accelerates V600EBRAF-driven melanomagenesis
a. Trp53 mutations (wt: wild-type, white; mut: mutant, magenta) in non-UVR, UVR and UVR+SS tumours; ** p=0.017; Fisher Exact Test. b. Sanger sequencing confirming C>T, p.H39Y Trp53 mutation in UVR tumour 2. c. Trp53 immunostaining in non-UVR Tumour 1 (Trp53 wt), UVR Tumour 2 (Trp53 mut), UVR Tumour 3 (Trp53 wt), and UVR +SS Tumour 1 (Trp53 wt). Bar 50μm. d. Kaplan-Meier showing melanoma free survival in tamoxifen-treated CreERT2 and CreERT2/R172HTrp53 (control; n=42), V600EBRAF/non-UVR (n=35), V600EBRAF/R172HTrp53 (n=23) and V600EBRAF+UVR (n=19) mice. V600EBRAF/non-UVR vs. V600E BRAF/R172HTrp53, p<0.0001; V600EBRAF+UVR vs. V600EBRAF/R172HTrp53, p<0.0001; Log-rank Test. e. Median tumour numbers in tamoxifen-treated CreERT2/R172HTrp53 mice (R172HTrp53), V600EBRAF/non-UVR (V600EBRAF) and V600EBRAF/R172HTrp53 mice. The error bars show mean ± SD. ***p<0.0001, WRST. f. V600EBRAF/R172HTrp53 mouse with multiple tumours (white arrows). g. H&E from a V600EBRAF/R172HTrp53 tumour. Bar 0.5mm. h. Boxed area from Fig. 4g. Bar: 250μm. Inset black arrows: mitotic cells. Bar: 5μm. i. Proportion of C>T (G>A) transitions in TP53 wild-type (wt) or mutant (mut) human melanomas from the Broad Institute (***p=0.002, WRST) and TCGA (https://tcga-data.nci.nih.gov/tcga/; ****p=1.79E-05) datasets. The error bars show the lowest data still within 1.5 IQR of the lowest quartile and highest data within 1.5 IQR of the upper quartile.
See this image and copyright information in PMC

Comment in

  • UV and melanoma: the TP53 link.
    Choi YS, Fisher DE. Choi YS, et al. Cell Res. 2014 Oct;24(10):1157-8. doi: 10.1038/cr.2014.95. Epub 2014 Jul 18. Cell Res. 2014. PMID: 25033756 Free PMC article.
  • TP53 in the UV spotlight: a bona fide driver of melanoma.
    Hurlstone A, Wellbrock C. Hurlstone A, et al. Pigment Cell Melanoma Res. 2014 Nov;27(6):1010-1. doi: 10.1111/pcmr.12302. Epub 2014 Sep 2. Pigment Cell Melanoma Res. 2014. PMID: 25102761 No abstract available.

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