BRAF(V600E) MUTATION AND THE BIOLOGY OF PAPILLARY THYROID CANCER

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 (PZ0.0048), extra-thyroid invasion (P!0.0001), and cervical lymph nodal metastases (PZ0.0001). Multivariate logistic regression analysis confirmed that BRAF(V600E) was an independent predictor of extra-thyroid invasion (PZ0.0001) and cervical lymph nodal metastasis (PZ0.0005). The association between BRAF(V600E) and extra-thyroid invasion was also found in micro-PTCs (PZ0.006). In 60 classical PTCs, BRAF(V600E) was positively correlated with matrix metalloproteinase-9 expression (PZ0.0047), 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. Endocrine-Related Cancer (2008) 15 191–205 Introduction Thyroid cancer is the 8th most common malignancy in women (3% of all cancers in women) and this value doubles the prevalence of 15 years ago,when itwas 1.7% of all cancers, ranking 14th in the list. Indeed, thyroid cancer incidence has increased faster than any other malignancy (3.8% per year in the period 1992–2001). At present, the incidence of thyroid cancer is estimated between 5 and 8 cases per 105 inhabitants per year in developed countries (Akslen et al. 1993, Colonna et al. Endocrine-Related Cancer (2008) 15 191–205 Endocrine-Related Cancer (2008) 15 191–205 1351–0088/08/015–191 q 2008 Society for Endocrinology Printed in Great Britain DOI: 10.1677/ERC-07-0212 Online version via http://www.endocrinology-journals.org