Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma
Copyright policy )Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma
Although nearly half of human melanomas harbor oncogenic BRAF(V600E) mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) transposon-mediated mutagenesis drives melanoma progression in Braf(V600E) mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more highly connected to one another than predicted by chance, indicating that SB targets cooperative genetic networks in melanoma. Human orthologs of >500 CCGs are enriched for mutations in human melanoma or showed statistically significant clinical associations between RNA abundance and survival of patients with metastatic melanoma. We also functionally validate CEP350 as a new tumor-suppressor gene in human melanoma. SB mutagenesis has thus helped to catalog the cooperative molecular mechanisms driving BRAF(V600E) melanoma and discover new genes with potential clinical importance in human melanoma.
- Dignity Health United States
- University of Iowa United States
- University of California, San Francisco United States
- University of Auckland New Zealand
- UCSF Helen Diller Family Comprehensive Cancer Center United States
Male, Mice, Inbred C3H, Mice, 129 Strain, Mice, Transgenic, Mice, SCID, Mice, Inbred C57BL, Gene Frequency, Mice, Inbred NOD, Cell Line, Tumor, DNA Transposable Elements, Microtubule Proteins, Animals, Humans, Exome, Female, Gene Regulatory Networks, Genes, Tumor Suppressor, Genetic Predisposition to Disease, Melanoma, Genetic Association Studies
Male, Mice, Inbred C3H, Mice, 129 Strain, Mice, Transgenic, Mice, SCID, Mice, Inbred C57BL, Gene Frequency, Mice, Inbred NOD, Cell Line, Tumor, DNA Transposable Elements, Microtubule Proteins, Animals, Humans, Exome, Female, Gene Regulatory Networks, Genes, Tumor Suppressor, Genetic Predisposition to Disease, Melanoma, Genetic Association Studies
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