BRAF mutation assessment in papillary thyroid cancer: are we ready to use it in clinical practice?

Abstract

In 2002, large-scale genomic screens allowed uncovering the occurrence of BRAF mutations in melanomas (67 %), colon carcinomas (12 %), and ovarian tumors (14 %) [1]. In the subsequent years, constitutively activating mutations in the BRAF oncogene, encoding a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway, have been reported in papillary thyroid carcinomas (PTC) (44 %) [2] and in hairy cell leukemias (100 %) [3]. Accordingly, the impact of BRAF mutation on clinical outcome has been extensively exploited in a variety of cancers, often resulting in controversial or unsettled findings. A T-to-A transversion at nucleotide 1799, which results in a valine to glutamate substitution at residue 600 (BRAF), is by far the most common mutation in differentiated thyroid cancer (DTC) [2]; however, it has been found as well in a fraction of poorly differentiated (PDTC) (10–15 %) and anaplastic thyroid carcinomas (ATC) (10–44 %) [4, 5]. The BRAF mutation’s high prevalence and detection easiness have facilitated the understanding of its pathogenetic, diagnostic, prognostic, and therapeutic roles in thyroid tumors. Experimental studies with transgenic mice characterized by thyroid-targeted expression of the oncogene consistently indicated that BRAF is a clonal-initiating event in thyroid follicular cell carcinogenesis [6]. Mutual exclusivity in PTCs of the most common genetic mutations, including BRAF and RAS mutations and RET/PTC rearrangements, indicate that each event is self-sufficient to constitutively activate the tumor-initiating MAPK pathway [6]. Conversely, more recently, a study that used pyrosequencing to determine the percentage of mutant BRAF alleles in conventional PTCs concluded that BRAF is a rare clonal event and more often a nonclonal mutation, occurring late during PTC progression [7]. If confirmed, this finding would have important ramifications because it would undermine the rationale for using therapies targeted against this oncoprotein. An intense scientific debate is ongoing on this topic [8] and, hopefully, it will help in clarifying this controversy soon. Another important question is if BRAF mutation might have a diagnostic role as malignant marker in a thyroid nodule aspirate, especially in the case of indeterminate fine-needle aspiration cytology (FNAC). The latter cytological picture occurs quite frequently (10–26 % of nodules) and harbors an intermediate risk of malignancy (14–48 %). Improvements of thyroid cytopathology by the introduction of thin core needle biopsy, with the assessment of the nodule capsule and the perinodular tissue, have appeared to ameliorate recognition of malignancy in cytologically indeterminate nodules [9]. Similarly, combination of nodule ultrasound features with measures of nodule stiffness, obtained by real-time elastography, has appeared to increase sensitivity for malignancy and to strengthen the selection of patients who do not need further diagnostic testing [10]. However, the analysis of diagnostic molecular markers on indeterminate FNAC specimens has caught the greatest interest. Search of DNA-based point mutations of BRAF has a sound biological rationale in view of its high frequency and driving role in PTCs and peculiar assay robustness due to DNA stability [6]. However, more than 50–60 % of DTCs do not harbor this molecular E. Puxeddu Department of Medicine, University of Perugia, Via Gambuli, 1, 06132 Perugia, Italy