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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.

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