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

Abstract

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 mutationpromoted 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. (Endocrine Reviews 28: 742-762, 2007) I. Introduction A. Thyroid cancer B. Clinicopathological risk evaluation of thyroid cancer C. MAPK pathway and its activating genetic alterations D. BRAF mutation in thyroid cancer II. Association of BRAF Mutation with High-Risk Clinicopathological Characteristics of PTC A. Data supporting a positive association B. Association of BRAF mutation with the most aggressive clinicopathological characteristics of PTC C. Studies with negative results III. Association of BRAF Mutation with Recurrence of PTC and Loss of Radioiodine Avidity in Recurrent Tumors A. Association with recurrence of PTC B. Association with loss of radioiodine avidity in recurrent PTC IV. Molecular Bases for BRAF Mutation-Promoted Invasiveness and Progression of PTC A. Unique role of BRAF mutation in thyroid tumorigenesis B. BRAF mutation-associated aberrant methylation and silencing of tumor suppressor genes C. Up-regulation of tumor-promoting molecules by BRAF mutation D. Silencing of thyroid iodide-metabolizing genes in PTC V. Testing of BRAF Mutation as a Potentially New Dimension to Risk Stratification and Clinical Management of PTC A. BRAF mutation as a novel prognostic molecular marker for PTC B. Potential utility of BRAF mutation in guiding medical management of PTC C. Value of preoperative testing of BRAF mutation on fine-needle aspiration biopsy in patients with PTC D. Special usefulness of BRAF mutation in the management of conventionally low-stage PTC VI. BRAF Mutation and Related Signaling Pathways as Novel Therapeutic Targets for Thyroid Cancer A. MAPK pathway as a major therapeutic target B. MEK inhibitors as highly promising therapeutic agents for thyroid cancer C. Restoring the expression of thyroid iodide-metabolizing genes by suppressing MAPK pathway D. Targeting multiple signaling pathways in aggressive thyroid cancers VII. Concluding