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Influence of the BRAF V600E Mutation on Expression of Vascular Endothelial Growth Factor in Papillary Thyroid Cancer

Division of Endocrinology, Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Department of Internal Medicine (Y.S.J., J.H.S., K.H.K., J.C.L., S.Y.R., H.J.L., H.R., M.S.), and Departments of Pathology (S.L., J.-M.K.), and Surgery (J.Y.S.), Chungnam National University School of Medicine, Daejeon 301-721, Korea; and Department of Biochemistry (G.R.K.), Seonam University College of Medicine, Namwon 590-711, Korea

Address all correspondence and requests for reprints to: Minho Shong, M.D., Ph.D., Division of Endocrinology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 301-721, Korea. E-mail: minhos{at}cnu.ac.kr; or Jin Man Kim, M.D., Ph.D., Department of Pathology, Chungnam National University School of Medicine, Daejeon 301-721, Korea. E-mail: jinmank{at}cnu.ac.kr.

Context: The BRAF mutation may influence the expression patterns of molecular markers that are related to the development and progression of thyroid cancer.

Objective: The objective of the study was to investigate the effects of the BRAF V600E mutation on expression of galectin-3, cyclooxygenase-2, cyclin D1, p53, and vascular endothelial growth factor (VEGF) in papillary thyroid cancer (PTC).

Design, Setting, and Subjects: One hundred sixty-three PTC and 28 nodular hyperplasia patients were selected retrospectively. The presence of the BRAF V600E mutation and the level of expression of the molecular markers were determined.

Results: Of 161 PTC patients, 102 patients (63.4%) were BRAF V600E(+), and these cases had significantly larger tumor sizes (P = 0.01), compared with V600E(–) cases (n = 59, 36.6%). Although PTC tissues had higher expression levels of the selected molecular markers than nodular hyperplasia tissues, expression levels of several molecular markers in BRAF V600E(+) PTC were not significantly different from those of BRAF V600E(–) PTC. But VEGF was significantly up-regulated in BRAF V600E(+) PTC, compared with BRAF V600E(–) PTC. VEGF expression levels were strongly positively correlated to tumor size (P < 0.001), extrathyroidal invasion (P = 0.02), and tumor stage (P = 0.04). Multivariate analysis clearly showed that VEGF expression was up-regulated in BRAF V600E(+) PTC (odds ratio 2.5, confidence interval 1.1–5.6; P = 0.03).

Conclusions: BRAF V600E(+) PTC tended to have larger tumor volumes and higher expression of VEGF. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. The relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.

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