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Association of BRAF V600E Mutation with Poor Clinicopathological Outcomes in 500 Consecutive Cases of Papillary Thyroid Carcinoma

Departments of Surgery (C.L., R.G., C.U., A.P., P.B., M.M., G.M., P.M., F.B.) and Endocrinology (R.E.), University of Pisa, 56126 Pisa, Italy; and Dipartimento di Biologia e Patologia Cellulare e Molecolare (M.S.), Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, University Federico II, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Fulvio Basolo, Ph.D., M.D., Department of Surgery, Division of Pathology, Via Roma, 57, 56126 Pisa, Italy. E-mail: f.basolo{at}med.unipi.it.

Context: Because very few studies have examined the correlation between BRAF mutations and clinicopathological features of papillary thyroid carcinoma (PTC), we analyzed here a large and homogeneous cohort of patients with PTC for the presence of the BRAF mutation.

Objective: We examined BRAF mutations in a consecutive series of 500 PTC patients who underwent surgery in the Department of Surgery of the University of Pisa, and we correlated the presence of the mutation with clinicopathological parameters of the patients: age, gender, tumor size, presence of tumor capsule, extrathyroidal invasion, multicentricity, presence of node metastases, and tumor class.

Design: BRAF (exon 15) mutation was examined by PCR-single strand conformational polymorphism followed by DNA sequencing in laser-capture microdissected tissue samples.

Results: In this study, BRAF mutation was found in 219 of 500 cases (43.8%). In particular, we found the most common BRAF V600E mutation in 214 cases (42.8%), BRAF K601E mutation in three cases (0.6%), BRAF VK600–1E (0.2%) in one case, whereas in one case we found a new 14-bp deletion with concomitant 2-bp insertion, VKSR600–3del and T599I, respectively. BRAF V600E was associated with extrathyroidal invasion (P < 0.0001), multicentricity (P = 0.0026), presence of nodal metastases (P = 0.0009), class III vs. classes I and II (P < 0.00000006), and absence of tumor capsule (P < 0.0001), in particular in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (P = 0.0005) with BRAF V600E mutation.

Conclusions: Our data suggest that BRAF V600E mutation is associated with high-risk PTC and in particular in follicular variant with invasive tumor growth.

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