The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models

Jennifer Yen, Richard M. White, David C. Wedge, Peter Van Loo, Jeroen de Ridder, Amy Capper, Jennifer Richardson, David Jones, Keiran Raine, Ian R. Watson, Chang Jiun Wu, Jiqiu Cheng, Iñigo Martincorena, Serena Nik-Zainal, Laura Mudie, Yves Moreau, John Marshall, Manasa Ramakrishna, Patrick Tarpey, Adam ShlienIan Whitmore, Steve Gamble, Calli Latimer, Erin Langdon, Charles Kaufman, Mike Dovey, Alison Taylor, Andy Menzies, Stuart McLaren, Sarah O'Meara, Adam Butler, Jon Teague, James Lister, Lynda Chin, Peter Campbell, David J. Adams, Leonard I. Zon, E. E. Patton, Derek L. Stemple, P. A. Futreal

Research output: Contribution to journalArticle

26 Scopus citations

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 BRAFV600E or NRASQ61K 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 BRAFV600E 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.

Original languageEnglish
Article numberR113
JournalGenome biology
Volume14
Issue number10
DOIs
StatePublished - Oct 23 2013
Externally publishedYes

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    Yen, J., White, R. M., Wedge, D. C., Van Loo, P., de Ridder, J., Capper, A., Richardson, J., Jones, D., Raine, K., Watson, I. R., Wu, C. J., Cheng, J., Martincorena, I., Nik-Zainal, S., Mudie, L., Moreau, Y., Marshall, J., Ramakrishna, M., Tarpey, P., ... Futreal, P. A. (2013). The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models. Genome biology, 14(10), [R113]. https://doi.org/10.1186/gb-2013-14-10-r113