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RET Codon 634 Mutations in Multiple Endocrine Neoplasia Type 2: Variable Clinical Features and Clinical Outcome

Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil; and Serviço de Endocrinologia e Metabologia DA, Universidade Federal do Paraná (H.G.), Curitiba 80060-900, Paraná, Brazil

Address all correspondence and requests for reprints to: Ana Luiza Maia, M.D., Ph.D., Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90035-003 Porto Alegre, Rio Grande do Sul, Brazil. E-mail: almaia{at}vortex.ufrgs.br.

Since the establishment of a protocol for molecular analysis of hereditary medullary thyroid carcinoma (MTC) in southern Brazil, in 1997, 17 independent families with RET germline mutation have been identified. Because neither molecular diagnosis nor the pentagastrin test were available before the establishment of this protocol, we had the opportunity to observe a large number of patients in whom the disease has evolved naturally without medical intervention, namely prophylactic thyroidectomy. We observed a wide spectrum in terms of clinical presentation and natural course of the disease even among genetically related individuals. Sixty-nine individuals from 12 different families presented a codon 634 mutation, the most prevailing missense mutation in our series. The specific mutations identified were C634Y (n = 49), C634R (n = 13), and C634W (n = 7). Individuals with the C634R mutation presented significantly more distant metastases at diagnosis than subjects with the C634Y or C634W mutations (54.5% vs. 19.4% vs. 14.3%, respectively, P = 0.03). Further analysis of the estimated cumulative frequency of lymph node and/or distant metastases by Kaplan-Meier curves showed that the appearance of lymph nodes and metastases occurred later in patients with C634Y than in those with C634R (P = 0.001). Our results suggest that specific nucleotide and amino acid exchanges at codon 634 might have a direct impact on tumor aggressiveness in MEN 2A syndrome.

This work was supported by Programa Núcleos de Excelência, Coordenação de Aperfeiçoamento de Pessoal, and Fundo de Incentivo a Pesquisa do Hospital de Clínicas de Porto Alegre, Brazil.

Current mailing address of all authors: Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90035-003 Porto Alegre, Rio Grande do Sul, Brazil.

Abbreviations: CLA, Cutaneous lichen amyloidosis; FMTC, familial MTC; HPT, hyperparathyroidism; MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; pheo, pheochromocytoma.

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