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This version published online on September 4, 2007
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-1179
A more recent version of this article appeared on November 1, 2007
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Submitted on May 29, 2007
Accepted on August 24, 2007

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

Cristiana Lupi, Riccardo Giannini, Clara Ugolini, Agnese Proietti, Piero Berti, Michele Minuto, Gabriele Materazzi, Rossella Elisei, Massimo Santoro, Paolo Miccoli, and Fulvio Basolo*

Department of Surgery, University of Pisa, Pisa-Italy (CL, RG, CU, AP, PB, MM, GM, PM, FB). Department of Endocrinology, University of Pisa, Italy (RE). Dipartimento di Biologia e Patologia Cellulare e Molecolare, University 'Federico II', c/o Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy (MS)

* To whom correspondence should be addressed. E-mail: f.basolo{at}med.unipi.it.

Context. As very few studies have examined the correlation between BRAF mutations and clinicopathologic 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 clinicopathologic parameters of the patients: age, gender, tumour size, presence of tumor capsule, extrathyroidal invasion, multicentricity, presence of node-metastases and tumor class.

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

Results. In this study, BRAF mutation was found in 219 out 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, while in one case we found a new 14 base pair deletion with concomitant two base pair 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. class I&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 tumour 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.
Key words: papillary thyroid carcinoma • BRAF • tumor capsule




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