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BRAF^V599E Mutation Is the Leading Genetic Event in Adult Sporadic Papillary Thyroid Carcinomas

Dipartimento di Medicina Interna (E.P., S.M., R.P., M.M., C.M., A.F., F.S.), Dipartimento di Scienze Chirurgiche (N.A.), Istituto di Anatomia e Istologia Patologica (A.C.), 2a Cattedra di Anatomia e Istologia Patologica (R.R.), Università di Perugia, Perugia; Dipartimento di Endocrinologia e Metabolismo (R.E., C.R., A.Pi.), Università di Pisa, Pisa; Istituto di Anatomia e Istologia Patologica (E.D.R., G.F.), Istituto di Endocrinologia (A.Po.), Università Cattolica del Sacro Cuore, Rome; and Dipartimento di Medicina Interna, Endocrinologia e Metabolismo e Biochimica (F.P.), Università di Siena, Siena, Italy

Address all correspondence and requests for reprints to: Efisio Puxeddu, M.D., Ph.D., Dipartimento di Medicina Interna, Sezione di Medicina Interna e Scienze Endocrine e Metaboliche, via E. dal Pozzo, 06126 Perugia, Italy. E-mail: efisio{at}dimisem.med.unipg.it.

Activating mutations of BRAF have been identified in a variety of human cancers, most notably melanomas and papillary thyroid carcinomas (PTCs). The aim of the present study was to disclose the role of BRAF mutations in thyroid carcinoma development.

Seventy-two thyroid tumors, including 60 PTCs, six follicular adenomas, five follicular carcinomas, and one anaplastic carcinoma, were studied. BRAF mutation screening focused on exon 15 and exon 11 of the gene by single-stranded conformational polymorphism and sequence analysis. Search of RET/PTC expression was conducted with the RT-PCR technique.

The molecular genetic study of the BRAF gene showed the presence of a missense thymine to adenine transversion at nucleotide 1796, resulting in the V599E substitution, in 24 of 60 PTCs (40%), none of six follicular adenomas, and none of five follicular carcinomas or one anaplastic carcinoma. Moreover, nine of 60 PTCs (15%) presented RET/PTC expression. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). On the contrary, no link could be detected between expression of BRAF^V599E and age at diagnosis, gender, dimension, and local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, and multifocality of the disease.

These data clearly confirm that BRAF^V599E is the more common genetic alteration found to date in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.

Abbreviations: A, Adenine; AC, anaplastic carcinoma; FA, follicular adenoma; FTC, follicular carcinoma; MEK, MAPK kinase; PTC, papillary thyroid carcinoma; SSCP, single-stranded conformational polymorphism; T, thymine.

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