Melanoma genome evolution across species

BMC Genomics

Research Article

Emily R. Kansler¹  Alexandra Yin¹  Erin M. Langdon¹  Theresa Simon-Vermot¹  Richard M. White²  William Lee³  Marc Attiyeh⁴  Olivier Elemento⁵  Akanksha Verma⁵ 

[1] Memorial Sloan Kettering Cancer Center, Cancer Biology & Genetics, New York, USA;Memorial Sloan Kettering Cancer Center, Cancer Biology & Genetics, New York, USA;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA;Memorial Sloan Kettering Cancer Center, Computational Biology, New York, USA;Memorial Sloan Kettering Cancer Center, The David M. Rubenstein Center for Pancreatic Cancer Research, New York, USA;Weill-Cornell Medical College, Institute for Computational Biomedicine, New York, USA;

关键词: Cancer;    Zebrafish;    Drug-resistance;    Melanoma;   

DOI  :  10.1186/s12864-017-3518-8

 received in 2016-09-24, accepted in 2017-01-26,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2017