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[Cancer Research 63, 1454-1457, April 1, 2003]
© 2003 American Association for Cancer Research


Advances in Brief

High Prevalence of BRAF Mutations in Thyroid Cancer

Genetic Evidence for Constitutive Activation of the RET/PTC-RAS-BRAF Signaling Pathway in Papillary Thyroid Carcinoma1

Edna T. Kimura, Marina N. Nikiforova, Zhaowen Zhu, Jeffrey A. Knauf, Yuri E. Nikiforov and James A. Fagin2

Division of Endocrinology and Metabolism [E. T. K., J. A. K., J. A. F.] and Department of Pathology [M. N. N., Z. Z., Y. E. N.], University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Thyroid papillary cancers (PTCs) are associated with activating mutations of genes coding for RET or TRK tyrosine kinase receptors, as well as of RAS genes. Activating mutations of BRAF were reported recently in most melanomas and a small proportion of colorectal tumors. Here we show that a somatic mutation of BRAF, V599E, is the most common genetic change in PTCs (28 of 78; 35.8%). BRAFV599E mutations were unique to PTCs, and not found in any of the other types of differentiated follicular neoplasms arising from the same cell type (0 of 46). Moreover, there was no overlap between PTC with RET/PTC, BRAF, or RAS mutations, which altogether were present in 66% of cases. The lack of concordance for these mutations was highly unlikely to be a chance occurrence. Because these signaling proteins function along the same pathway in thyroid cells, this represents a unique paradigm of human tumorigenesis through mutation of three signaling effectors lying in tandem.




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