BRAF Mutation in Papillary Thyroid Carcinoma: Pathogenic Role and Clinical Implications

Abstract

Papillary thyroid cancer (PTC) is the most common endocrine malignancy, accounting for 85-90% of all thyroid cancers. Genetic alternations involving the mitogen-activated protein kinase (MAPK) pathway are frequently demonstrated in PTC, such as RET/PTC, RAS, and B-type Raf kinase (BRAF) mutations. Over 90% of BRAF mutations are T1799A, resulting in a BRAF(V600E) mutation. BRAF(V600E) is present in approximately 50% of PTC and also found in aggressive histologic variants and PTC-derived anaplastic thyroid cancer, but is rare in follicular variants, and not found in follicular thyroid cancer. The tumorigenic role of BRAF(V600E) in the development of PTC was documented in thyroid-targeted BRAF(V600E) transgenic mice, and rat thyroid cells overexpressed with BRAF(V600E) suggested that BRAF(V600E) is an initiator of tumorigenesis and is required for tumor progression in PTC. Most clinical studies have demonstrated an association of BRAF(V600E) mutation with aggressive clinicopathologic characteristics and high tumor recurrence, although the results are controversial. The association is also observed in patients with papillary thyroid microcarcinomas and low-risk PTC. As a highly specific and unique mutation in PTC, testing for BRAF(V600E) in fine-needle aspiration specimens has been shown to refine the diagnostic accuracy of PTC in indeterminate cytology. Preoperative BRAF(V600E) analysis in low-risk patients may provide important value for prognostication, and these patients might benefit from receiving more intensive management and frequent follow-up. BRAF-targeted therapies have been developed to treat various human cancers including advanced thyroid cancers. Preclinical results are encouraging, but the anticancer effects of clinical trials are disappointing. Studies of multi-kinase inhibitors and/or combination with other regimens are underway in the treatment of advanced thyroid cancers. In this article, we review the pathogenesis of PTC, and the clinical implications of BRAF(V600E) mutation in the diagnosis, prognosis and potential targeted therapeutic strategies for thyroid cancers.