Abstract
BackgroundCancer genomes evolve in both space and time, which contributes to the genetic heterogeneity that underlies tumor progression and drug resistance. In human melanoma, identifying mechanistically important events in tumor evolution is hampered due to the high background mutation rate from ultraviolet (UV) light. Cross-species oncogenomics is a powerful tool for identifying these core events, in which transgenically well-defined animal models of cancer are compared to human cancers to identify key conserved alterations.ResultsWe use a zebrafish model of tumor progression and drug resistance for cross-species genomic analysis in melanoma. Zebrafish transgenic tumors are initiated with just 2 genetic lesions, BRAFV600E and p53-/-, yet take 4–6 months to appear, at which time whole genome sequencing demonstrated >3,000 new mutations. An additional 4-month exposure to the BRAF inhibitor vemurafenib resulted in a highly drug resistant tumor that showed 3 additional new DNA mutations in the genes BUB1B, PINK1, and COL16A1. These genetic changes in drug resistance are accompanied by a massive reorganization of the transcriptome, with differential RNA expression of over 800 genes, centered on alterations in cAMP and PKA signaling. By comparing both the DNA and mRNA changes to a large panel of human melanomas, we find that there is a highly significant enrichment of these alterations in human patients with vemurafenib resistant disease.ConclusionsOur results suggest that targeting of alterations that are conserved between zebrafish and humans may offer new avenues for therapeutic intervention. The approaches described here will be broadly applicable to the diverse array of cancer models available in the zebrafish, which can be used to inform human cancer genomics.
Highlights
Cancer genomes evolve in both space and time, which contributes to the genetic heterogeneity that underlies tumor progression and drug resistance
ZMEL1 line derivation For these studies, we utilized the previously developed zebrafish melanoma model [6, 7], in which human oncogenic BRAFV600E is expressed under the melanocyte specific mitfa promoter
These animals are completely devoid of melanocytes due to the mitfa mutation [12], but harbor the capacity for melanoma initiation when mosaically injected with a transgene containing an mitfa and GFP rescue cassette
Summary
Cancer genomes evolve in both space and time, which contributes to the genetic heterogeneity that underlies tumor progression and drug resistance. Large-scale advances in genomic profiling of human cancers has enabled the identification of thousands of new potential genetic and epigenetic targets [1]. In melanoma, this effort has been complicated by the relatively high background mutation rate induced by ultraviolet light (UV) [2]. This is likely due to several factors: 1) a variety of genes can act as initiating events (i.e. BRAF, NRAS, c-Kit), 2) a lack of knowledge of the cell of origin of individual tumors, and 3) individual germline variation in DNA repair mechanisms. As the tumors evolve under drug therapy (i.e. BRAF inhibitors or immunotherapy), each of these factors make it increasingly challenging to identify key genomic events promoting such evolution
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