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BRAF Mutation in Papillary Thyroid Cancer: Pathogenic Role, Molecular Bases, and Clinical Implications

Division of Endocrinology and Metabolism, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Correspondence: Address all correspondence and requests for reprints to: Michael Mingzhao Xing, M.D., Ph.D., Associate Professor of Medicine and Oncology, Division of Endocrinology and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287. E-mail: mxing1{at}jhmi.edu

In recent years, the T1799A B-type Raf kinase (BRAF) mutation in thyroid cancer has received enthusiastic investigation, and significant progress has been made toward understanding its tumorigenic role and clinical significance. Among various thyroid tumors, this mutation occurs uniquely in papillary thyroid cancer (PTC), the most common endocrine malignancy, and some apparently PTC-derived anaplastic thyroid cancers. Many studies have found this mutation to be associated with those clinicopathological characteristics of PTC that are conventionally known to predict tumor progression and recurrence, including, for example, old patient age, extrathyroidal invasion, lymph node metastasis, and advanced tumor stages. Direct association of BRAF mutation with the clinical progression, recurrence, and treatment failure of PTC has also been demonstrated. The BRAF mutation has even been correlated with PTC recurrence in patients with conventionally low-risk clinicopathological factors. Some molecular mechanisms determining BRAF mutation-promoted progression and the aggressiveness of PTC have recently been uncovered. These include the down-regulation of major tumor suppressor genes and thyroid iodide-metabolizing genes and the up-regulation of cancer-promoting molecules, such as vascular endothelial growth factor, matrix metalloproteinases, nuclear transcription factor B, and c-Met. Thus, BRAF mutation represents a novel indicator of the progression and aggressiveness of PTC. Significant advances have also occurred in the preclinical testing of new therapeutic strategies targeting the MAPK pathway aberrantly activated by BRAF mutation and other related mutations. New mitogen extracellular kinase (MEK) inhibitors developed recently are particularly promising therapeutic agents for thyroid cancer. With these advances, it has become clearer that BRAF mutation will likely have significant impact on the clinical management of PTC.

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