The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models
1 Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
2 Memorial Sloan Kettering Cancer Center and Weill-Cornell Medical College, New York, NY 10065, USA
3 Department of Human Genetics, VIB and University of Leuven, B-3000, Leuven, Belgium
4 Delft Bioinformatics Lab, Delft University of Technology, Delft 2628CD, the Netherlands
5 MRC Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit and Edinburgh Cancer Research Centre, Edinburgh EH4 2XU, UK
6 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
7 Department of Electrical Engineering, University of Leuven, B-3001, Leuven, Belgium
8 Dana Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
9 Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298-0033, USA
10 Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Genome Biology 2013, 14:R113 doi:10.1186/gb-2013-14-10-r113Published: 23 October 2013
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.
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.
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.