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The Heterogeneous Distribution of BRAF Mutation Supports the Independent Clonal Origin of Distinct Tumor Foci in Multifocal Papillary Thyroid Carcinoma

Departments of Surgery (R.G., C.U., C.L., A.P., P.B., 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 (G.S., M.S.), University "Federico II", c/o Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, 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: Papillary thyroid carcinoma (PTC) is frequently multifocal. Independent PTC foci may occur either from intraglandular metastases from a single dominant tumor or as unrelated neoplastic clones. In rare cases, the simultaneous presence of PTC foci of different histopathological subtypes points to independent sites of tumor formation.

Objectives: We examined the pattern of BRAF mutations in noncontiguous tumor foci and node metastases from 69 patients affected by multicentric PTC. These included 19 cases characterized by the simultaneous presence of different PTC histopathological variants.

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

Results: Discordant patterns of BRAF mutation were found in about 40% of the multifocal PTCs. In node metastases, BRAF mutations were, in most but not all the cases, concordant with the dominant tumor. A discordant pattern of BRAF mutation was also found in about 50% of the cases in which multiple foci of different histopathological variants were present.

Conclusions: The heterogeneous distribution of BRAF mutations suggests that discrete tumor foci in multifocal PTC may occur as independent tumors. This information has to be considered in the design of targeted therapeutic approaches with BRAF pathway inhibitors.

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