Roles of RAS and BRAF mutations in thyroid carcinogenesis

Papillary carcinoma and follicular carcinoma are types of differentiated thyroid carcinomas, develop from the same thyroid follicular epithelial cells and show distinct biological behavior. Although several studies have demonstrated differences in the biological characteristics of these carcinomas, little is known about the genetic backgrounds that underlie these differences. The clarification of the genetic background can lead to the understanding of thyroid carcinogenesis, proper therapeutic strategies, and development of the molecular targeting drugs. Recently, aberrant activation of RAS-RAF-MEK-MAP kinase signaling pathway is frequently found in thyroid carcinoma. The pathway transmits a mitogenic signal to the nucleus, and constitutive activation of the pathway is thought to promote uncontrolled cell division. In our series, BRAF mutation was detected exclusively in papillary carcinoma (54%), and was exclusively V599E (a single nucleotide change of A-T at nucleotide 1796). NRAS mutation was observed in follicular carcinoma (50%) and in anaplastic carcinoma (28%), and was exclusively Q61R (a single nucleotide change of A-G at nucleotide 182). No mutations were found in KRAS or HRAS. In this chapter, we explain the role of RAS-RAF-MEK-MAP kinase pathway in carcinogenesis of the thyroid and its clinical implication based on our study. In addition, we review the current knowledge in this field.