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BRAF fusions identified in melanomas have variable treatment responses and phenotypes
- Source :
- Oncogene. 38:1296-1308
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- Oncogenic BRAF fusions have emerged as an alternate mechanism for BRAF activation in melanomas and other cancers. A number of BRAF fusions with different 5' gene partners and BRAF exon breakpoints have been described, but the effects of different partners and breakpoints on cancer phenotypes and treatment responses has not been well characterized. Targeted RNA sequencing was used to screen 60 melanoma patient-derived xenograft (PDX) models for BRAF fusions. We identified three unique BRAF fusions, including a novel SEPT3-BRAF fusion, occurring in four tumors (4/60, 6.7%), all of which were "pan-negative" (lacking other common mutations) (4/18, 22.2%). The BRAF fusion PDX models showed variable growth rates and responses to MAPK inhibitors in vivo. Overexpression of BRAF fusions identified in our study, as well as other BRAF fusions previously identified in melanomas, resulted in a high degree of variability in 2D proliferation and 3D invasion between the different fusions. While exogenously expressed BRAF fusions all responded to MAPK inhibition in vitro, we observed potential differences in signaling and feedback mechanisms. In summary, BRAF fusions are actionable therapeutic targets, however there are significant differences in phenotypes, treatment responses, and signaling which may be clinically relevant.
- Subjects :
- 0301 basic medicine
Cancer Research
endocrine system diseases
Biology
medicine.disease_cause
03 medical and health sciences
Exon
0302 clinical medicine
Genetics
medicine
skin and connective tissue diseases
neoplasms
Molecular Biology
Gene
Regulation of gene expression
Mutation
Melanoma
Breakpoint
Cancer
medicine.disease
Phenotype
digestive system diseases
enzymes and coenzymes (carbohydrates)
030104 developmental biology
030220 oncology & carcinogenesis
Cancer research
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi...........cfa03962c618067f5101e2dccd98ba99
- Full Text :
- https://doi.org/10.1038/s41388-018-0514-7