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dc.date.accessioned2018-06-06T10:42:00Z
dc.date.issued2014-07
dc.identifierhttp://publications.icr.ac.uk/13540/
dc.identifier.citationNATURE, 2014, 511 (7510), pp. 478 - +
dc.identifier.issn0028-0836
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1743
dc.description.abstractCutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear(1,2). The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event(3). 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(4). 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 inhuman melanoma. Thus, we provide mechanistic insight into epidemiological data linking UVR to acquired naevi in humans(5). 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.
dc.format.extent478 - +
dc.languageeng
dc.language.isoeng
dc.subjectMELANOCYTIC NEVI SEQUENCING DATA P53 GAIN MUTATIONS MICE SUNSCREEN CANCER EXPRESSION PREVENTION EXPOSURE
dc.titleUltraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53
dc.typeJournal Article
rioxxterms.licenseref.startdate2014-07
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNATURE
pubs.issue7510
pubs.notesISI Document Delivery No.: AL7SO Times Cited: 0 Cited Reference Count: 38 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 Cancer Research UK [C107/A10433, C5759/A12328, A13540, A17240]; Wenner-Gren Foundations; Stockholm; Teggerstiftelsen; FEBS Long-Term Fellowship 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. 0 NATURE PUBLISHING GROUP LONDON NATURE
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Signal Transduction
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Signal Transduction
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.volume511
pubs.embargo.termsNot known
icr.researchteamSignal Transductionen_US
icr.researchteamTargeted Therapyen_US
dc.contributor.icrauthorMarais, Richard Malcolmen
dc.contributor.icrauthorPedersen, Malinen


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