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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Functional characterization of the novel T599I-VKSRdel BRAF mutation in a follicular variant papillary thyroid carcinoma.

CONTEXT: Mutations in BRAF are rare in the follicular variant of papillary thyroid carcinoma (FV-PTC). OBJECTIVE: We identified and functionally characterized a novel T599I-VKSR(600-603)del BRAF mutation in a FV-PTC patient. We analyzed in vitro the effects of this novel mutation in comparison with other thyroid cancer-associated mutations. DESIGN: Expression vectors for the BRAF mutants were generated and their in vitro kinase activity, signaling along the MAPK pathway, and capability of stimulating transcription from an AP1-responsive reporter evaluated. RESULTS: BRAF kinase and signaling were increased to a similar extent by the T599I-VKSR (600-603)del, V600E, and K601E mutations. Instead, the G474R, a mutation previously found in a FV-PTC, knocked down the BRAF kinase and its intracellular signaling. Some cancer-associated low-activity BRAF mutants stimulate the MAPK cascade via CRAF; however, the G474R protein lacked also this property. CONCLUSION: The T599I-VKSR(600-603)del is a novel gain-of-function mutation that targets BRAF in FV-PTC. Moreover, G474R is the first example of a mutation knocking down enzymatic BRAF activity in a FV-PTC. These findings underscore the importance of functional studies to characterize the role of BRAF mutations associated with thyroid cancer.[1]


  1. Functional characterization of the novel T599I-VKSRdel BRAF mutation in a follicular variant papillary thyroid carcinoma. De Falco, V., Giannini, R., Tamburrino, A., Ugolini, C., Lupi, C., Puxeddu, E., Santoro, M., Basolo, F. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
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