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Endocrinologia, Dipartimento di Medicina Interna e Medicina Specialistica, University of Catania, PO Garibaldi Nesima, Via Palermo 636, 95122 Catania, Italy¹ Sezione di Endocrinologia, Dipartimento Clinico-Sperimentale di Medicina e Farmacologia, Azienda Ospedaliera Universitaria Policlinico, University of Messina, Via Consolare Valeria, 98122 Messina, Italy² Unità Operativa di Anatomia Patologica, Ospedale Vittorio Emanuele, Via Plebiscito 628, 95124 Catania, Italy³ Divisione di Endocrinologia and ⁴ Servizio di Anatomia Patologica, Ospedale Cervello, Via Trabucco 180, 90146 Palermo, Italy⁵ Dana-Farber Cancer Institute, and Pathology Department, Medical Oncology and Center For Molecular Oncologic Pathology, Harvard Medical School, Brigham and Women's Hospital, 44 Binney Street, 02115 Boston, Massachusetts, USA⁶ Sezione di Endocrinologia, Dipartimento di Oncologia Sperimentale Clinica, Università degli Studi di Palermo, Policlinico, Via del Vespro 129, 90127 Palermo, Italy⁷ Dipartimento di Medicina Sperimentale e Farmacologia, Azienda Ospedaliera Universitaria Policlinico, University of Messina, Via Consulare Valeria, 98122 Messina, Italy⁸ Endocrinologia, Dipartimento di Medicina Sperimentale e Clinica, University of Catanzaro, Viale Europa, 88100 Germaneto Catanzaro, Italy

(Correspondence should be addressed to R Vigneri; Email: vigneri{at}unict.it)

BRAF^(V600E) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80–90% of all thyroid cancers. We evaluated the relationship between BRAF^(V600E) and tumor, host, and environmental factors in PTCs from all geographical areas of Sicily. By PCR, BRAF^(V600E) was investigated in a series of 323 PTCs diagnosed in 2002–2005. The correlation between clinicopathological tumor, host, and environmental characteristics and the presence of BRAF^(V600E) were evaluated by both univariate and multivariate analyses. BRAF^(V600E) was found in 38.6% PTCs, with a 52% frequency in the classical PTCs and 26.4% in the tall cell variant. Univariate analysis indicated that BRAF^(V600E) was associated with greater tumor size (P=0.0048), extra-thyroid invasion (P<0.0001), and cervical lymph nodal metastases (P=0.0001). Multivariate logistic regression analysis confirmed that BRAF^(V600E) was an independent predictor of extra-thyroid invasion (P=0.0001) and cervical lymph nodal metastasis (P=0.0005). The association between BRAF^(V600E) and extra-thyroid invasion was also found in micro-PTCs (P=0.006). In 60 classical PTCs, BRAF^(V600E) was positively correlated with matrix metalloproteinase-9 expression (P=0.0047), suggesting a possible mechanism for BRAF^(V600E) effect on PTC invasiveness. No association was found between BRAF^(V600E) and patient age, gender, or iodine intake. In contrast, a strong association was found with residency in Eastern Sicily (P<0.0001 compared with Western Sicily). These results indicate that BRAF^(V600E) mutation is a marker of aggressive disease in both micro- and macro-PTCs. Moreover, for the first time, a possible link between BRAF^(V600E) mutation and environmental carcinogens is suggested.

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