title: Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.
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.
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Amaya
authors.initials: A
authors.lastname: Viros
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Berta
authors.initials: B
authors.lastname: Sanchez-Laorden
authors.affiliation: Signal Transduction Team, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
authors.forename: Malin
authors.initials: M
authors.lastname: Pedersen
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Furney
authors.affiliation: Signal Transduction Team, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
authors.forename: Joel
authors.initials: J
authors.lastname: Rae
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Hogan
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ejiama
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Maria Romina
authors.initials: MR
authors.lastname: Girotti
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.|Histopathology, Royal Surrey County Hospital, Egerton Road, Guildford, GU2 7XX UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Cook
authors.affiliation: Signal Transduction Team, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dhomen
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.|Signal Transduction Team, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
mesh_terms: D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000528:radiation effects*; D004249:DNA Damage / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008545:Melanoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis / Q000235:genetics / Q000528:radiation effects*; D009154:Mutation / Q000235:genetics / Q000528:radiation effects; D009506:Nevus / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013471:Sunburn / Q000150:complications / Q000209:etiology / Q000235:genetics; D013473:Sunscreening Agents / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*; D000096142:Cutaneous Malignant Melanoma
chemical_list: D013473:Sunscreening Agents; D016159:Tumor Suppressor Protein p53; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf