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Functional Characterization of the Novel T599I-VKSRdel BRAF Mutation in a Follicular Variant Papillary Thyroid Carcinoma

Istituto di Endocrinologia ed Oncologia Sperimentale del CNR (V.D.F., A.T., M.S.), Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, 80131 Naples, Italy; Department of Surgery (R.G., C.U., C.L., F.B.), University of Pisa, 56127 Pisa, Italy; and Dipartimento di Medicina Interna (E.P.), Università degli Studi di Perugia, 06123 Perugia, Italy

Address all correspondence and requests for reprints to: Massimo Santoro, Dipartimento di Biologia e Patologia Cellulare e Molecolare, "L. Califano", Universita’ Federico II di Napoli, via S. Pansini 5, 80131 Naples, Italy. E-mail: masantor{at}unina.it.

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.

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