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A Novel Germ-Line Point Mutation in RET Exon 8 (Gly⁵³³Cys) in a Large Kindred with Familial Medullary Thyroid Carcinoma

Laboratory of Molecular Endocrinology, Division of Endocrinology (A.M.A.D.S., R.M.B.M., M.R.D.D.S., J.M.C.), and J. F. Perez Genomic Center (R.M.B.M., M.R.D.D.S.), Department of Medicine; Division of Genetics (J.M.C.), Department of Morphology and Institute of Pediatric Oncology (S.R.C.T.), Department of Pediatrics, Escola Paulista de Medicina, Federal University of Sao Paulo; Division of Genetics and Biotechnology (A.M.A.D.S.), Santo Andre Foundation; and Service of Head and Neck Surgery (M.B.D.C.), Heliopolis Hospital, 04039-032 Sao Paulo, Brazil

Address all correspondence and requests for reprints to: Janete M. Cerutti, Ph.D., Laboratory of Molecular Endocrinology, Division of Endocrinology, Department of Medicine, Universidade Federal de Sao Paulo, Rua Pedro de Toledo 781, 12 andar, 04039-032 Sao Paulo SP, Brazil. E-mail: cerutti-endo{at}pesquisa.epm.br.

Familial medullary thyroid carcinoma is related to germ-line mutations in the RET oncogene, mainly in cysteine codon 10 or 11, whereas noncysteine mutations in codons 13–15 are rare. We now report a new missense point mutation in exon 8 of the RET gene (1597GT) corresponding to a Gly⁵³³Cys substitution in the cystein-rich domain of RET protein in 76 patients from a 6-generation Brazilian family with 229 subjects, with ascendants from Spain. It is likely that the mutation causes familial medullary thyroid carcinoma (FMTC), because no other mutation was found in RET, the mutation cosegregates with medullary thyroid carcinoma (MTC) or C cell hyperplasia (CCH) in patients subjected to surgery, and family members without the mutation are clinically unaffected. The histological analysis of 35 cases submitted to thyroidectomy revealed that 21 patients had MTC after the age of 40 yr and 8 before the age of 40 yr, 4 presented MTC or CCH before the age of 18 yr, 2 died due to MTC at the age of 53 and 60 yr, and CCH was found in a 5-yr-old child, suggesting a clinical heterogeneity. To improve the diagnosis of FMTC, analysis of exon 8 of RET should be considered in families with no identified classical RET mutations.

This work was supported by grants from the Sao Paulo State Research Foundation [FAPESP Grants 99/03688-4 and 01/00246 (to R.M.B.M. and J.M.C.) and 00/03442-2 (to M.R.D.D.S.)], Brazilian Research Council (R.M.B.M. is investigator under Contract 300879/1998–1999), and CAPES-Brazilian Department of Education (J.M.C. is investigator under Contract 1946/01-3).

Abbreviations: CCH, C Cell hyperplasia; FMTC, familial medullary thyroid carcinoma; MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; Pg, pentagastrin; sCT, serum calcitonin; SNP, single nucleotide polymorphism.

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