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 ∼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.