The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models.
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Authors
Yen, Jennifer
White, Richard M
Wedge, David C
Van Loo, Peter
de Ridder, Jeroen
Capper, Amy
Richardson, Jennifer
Jones, David
Raine, Keiran
Watson, Ian R
Wu, Chang-Jiun
Cheng, Jiqiu
Martincorena, Iñigo
Nik-Zainal, Serena
Mudie, Laura
Moreau, Yves
Marshall, John
Ramakrishna, Manasa
Tarpey, Patrick
Shlien, Adam
Whitmore, Ian
Gamble, Steve
Latimer, Calli
Langdon, Erin
Kaufman, Charles
Dovey, Mike
Taylor, Alison
Menzies, Andy
McLaren, Stuart
O'Meara, Sarah
Butler, Adam
Teague, Jon
Lister, James
Chin, Lynda
Campbell, Peter
Adams, David J
Zon, Leonard I
Patton, E Elizabeth
Stemple, Derek L
Futreal, P Andy
Publication Date
2013Journal Title
Genome Biol
ISSN
1474-760X
Publisher
Springer Science and Business Media LLC
Volume
14
Issue
10
Pages
R113
Language
eng
Type
Article
Physical Medium
Print
Metadata
Show full item recordCitation
Yen, J., White, R. M., Wedge, D. C., Van Loo, P., de Ridder, J., Capper, A., Richardson, J., et al. (2013). The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models.. Genome Biol, 14 (10), R113. https://doi.org/10.1186/gb-2013-14-10-r113
Abstract
BACKGROUND: Melanoma is the most deadly form of skin cancer. Expression of oncogenic BRAF or NRAS, which are frequently mutated in human melanomas, promote the formation of nevi but are not sufficient for tumorigenesis. Even with germline mutated p53, these engineered melanomas present with variable onset and pathology, implicating additional somatic mutations in a multi-hit tumorigenic process. RESULTS: To decipher the genetics of these melanomas, we sequence the protein coding exons of 53 primary melanomas generated from several BRAF(V600E) or NRAS(Q61K) driven transgenic zebrafish lines. We find that engineered zebrafish melanomas show an overall low mutation burden, which has a strong, inverse association with the number of initiating germline drivers. Although tumors reveal distinct mutation spectrums, they show mostly C > T transitions without UV light exposure, and enrichment of mutations in melanogenesis, p53 and MAPK signaling. Importantly, a recurrent amplification occurring with pre-configured drivers BRAF(V600E) and p53-/- suggests a novel path of BRAF cooperativity through the protein kinase A pathway. CONCLUSION: This is the first analysis of a melanoma mutational landscape in the absence of UV light, where tumors manifest with remarkably low mutation burden and high heterogeneity. Genotype specific amplification of protein kinase A in cooperation with BRAF and p53 mutation suggests the involvement of melanogenesis in these tumors. This work is important for defining the spectrum of events in BRAF or NRAS driven melanoma in the absence of UV light, and for informed exploitation of models such as transgenic zebrafish to better understand mechanisms leading to human melanoma formation.
Keywords
Animals, Animals, Genetically Modified, Zebrafish, Melanoma, Disease Models, Animal, Risk Factors, Ultraviolet Rays, Gene Amplification, Sequence Deletion, Homozygote, Genetic Heterogeneity, Mutation, Polymorphism, Single Nucleotide, INDEL Mutation, Gene Knockout Techniques, DNA Copy Number Variations
Identifiers
External DOI: https://doi.org/10.1186/gb-2013-14-10-r113
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286137
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