Alterations of the BRAF gene in thyroid tumors

BRAF belongs to the RAF family of protein kinases that are important components of the MAPK signaling pathway mediating cell growth, differentiation and survival. Activating point mutation of the BRAF gene resulting in V600E (previously designated as V599E) is a common event in thyroid papillary carcinoma, being found in approx 40% of this tumor. It has strong association with classical papillary carcinoma and tall cell and possibly Warthin-like variants. This mutation also occurs in thyroid poorly differentiated and anaplastic carcinomas, usually those containing areas of papillary carcinoma. Alterations in the BRAF gene do not overlap with RAS mutations and RET/PTC rearrangement, indicating that activation of one of the effectors of the MAPK pathway is sufficient for papillary thyroid carcinogenesis. Recently, another mechanism of BRAF activation has been identified, which involves chromosome 7q inversion that results in the AKAP9-BRAF fusion. It is rare in sporadic papillary carcinomas and is more common in tumors associated with radiation exposure. Yet another mechanism of BRAF activation may involve copy number gain, which is seen in a significant portion of thyroid follicular tumors of both conventional and oncocytic (Hürthle cell) types.