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Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.

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Title: Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.
Authors: Viros, Amaya, Sanchez-Laorden, Berta, Pedersen, Malin, Furney, Simon J., Rae, Joel, Hogan, Kate, Ejiama, Sarah, Girotti, Maria Romina, Cook, Martin, Dhomen, Nathalie, Marais, Richard
Source: Nature. 7/24/2014, Vol. 511 Issue 7510, p478-482. 5p.
Subjects: Ultraviolet radiation, BRAF genes, p53 protein, Melanoma, Somatic mutation
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. [ABSTRACT FROM AUTHOR]
Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.
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  Data: <searchLink fieldCode="AR" term="%22Viros%2C+Amaya%22">Viros, Amaya</searchLink><br /><searchLink fieldCode="AR" term="%22Sanchez-Laorden%2C+Berta%22">Sanchez-Laorden, Berta</searchLink><br /><searchLink fieldCode="AR" term="%22Pedersen%2C+Malin%22">Pedersen, Malin</searchLink><br /><searchLink fieldCode="AR" term="%22Furney%2C+Simon+J%2E%22">Furney, Simon J.</searchLink><br /><searchLink fieldCode="AR" term="%22Rae%2C+Joel%22">Rae, Joel</searchLink><br /><searchLink fieldCode="AR" term="%22Hogan%2C+Kate%22">Hogan, Kate</searchLink><br /><searchLink fieldCode="AR" term="%22Ejiama%2C+Sarah%22">Ejiama, Sarah</searchLink><br /><searchLink fieldCode="AR" term="%22Girotti%2C+Maria+Romina%22">Girotti, Maria Romina</searchLink><br /><searchLink fieldCode="AR" term="%22Cook%2C+Martin%22">Cook, Martin</searchLink><br /><searchLink fieldCode="AR" term="%22Dhomen%2C+Nathalie%22">Dhomen, Nathalie</searchLink><br /><searchLink fieldCode="AR" term="%22Marais%2C+Richard%22">Marais, Richard</searchLink>
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  Data: <searchLink fieldCode="DE" term="%22Ultraviolet+radiation%22">Ultraviolet radiation</searchLink><br /><searchLink fieldCode="DE" term="%22BRAF+genes%22">BRAF genes</searchLink><br /><searchLink fieldCode="DE" term="%22p53+protein%22">p53 protein</searchLink><br /><searchLink fieldCode="DE" term="%22Melanoma%22">Melanoma</searchLink><br /><searchLink fieldCode="DE" term="%22Somatic+mutation%22">Somatic mutation</searchLink>
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  Data: 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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