The RET p.G533C Mutation Confers Predisposition to Multiple Endocrine Neoplasia Type 2A in a Brazilian Kindred and Is Able to Induce a Malignant Phenotype In Vitro and In Vivo

Autor(es)

Oliveira, Mariana N. L. ^[1] ; Hemerly, Jefferson P. ^[1] ; Bastos, Andre U. ^[1] ; Tamanaha, Rosana ^[1] ; Latini, Flavia R. M. ^[1] ; Camacho, Cleber P. ^[2] ; Impellizzeri, Anelise ^[3] ; Maciel, Rui M. B. ^[2] ; Cerutti, Janete M. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Div Genet, Genet Bases Thyroid Tumors Lab, BR-04039032 Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Div Endocrinol, Mol Endocrinol Lab, BR-04039032 Sao Paulo - Brazil

^[3] Univ Fed Minas Gerais, Div Endocrinol, Belo Horizonte, MG - Brazil

• Tipo de documento: Artigo Científico
• Fonte: THYROID; v. 21, n. 9, p. 975-985, SEP 2011.
• Citações Web of Science: 18

Resumo

Background: We have previously described a p.G533C substitution in the rearranged during transfection (RET) oncogene in a large family with medullary thyroid carcinoma. Here, we explore the functional transforming potential of RET p.G533C mutation. Methods: Plasmids expressing RET mutants (p.G533C and p.C634Y) and RET wild type were stable transfected into a rat thyroid cell line (PCCL3). Biological and biochemical effects of RET p.G533C were investigated both in vitro and in vivo. Moreover, we report the first case of pheochromocytoma among the RET p.G533C-carriers in this Brazilian family and explore the RET mutational status in DNA isolated from pheochromocytoma. Results: Ectopic expression of RET p.G533C and p.C634Y activates RET/MAPK/ERK pathway at similar levels and significantly increased cell proliferation, compared with RET wild type. We additionally show that p.G533C increased cell viability, anchorage-independent growth, and micronuclei formation while reducing apoptosis, hallmarks of the malignant phenotype. RET p.G533C down-regulates the expression of thyroid specific genes in PCCL3. Moreover, RET p.G533C-expressing cells were able to induce liver metastasis in nude mice. Finally, we described two novel RET variants (G548V and S556T) in the DNA isolated from pheochromocytoma while they were absent in the DNA isolated from blood. Conclusions: Our in vitro and in vivo analysis indicates that this mutation confers a malignant phenotype to PCCL3 cells. These findings, in association with the report of first case of pheochromocytoma in the Brazilian kindred, suggest that this noncysteine mutation may be more aggressive than was initially considered. (AU)

• Processo FAPESP: 05/60330-8 - Marcadores moleculares no diagnóstico e prognóstico de pacientes com tumores da tiroide humana: transição da pesquisa básica para a clínica
• Beneficiário: Janete Maria Cerutti
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 06/60402-1 - Carcinoma medular da tiróide: revisitação à clínica, à biologia molecular, à bioquímica e à biologia do desenvolvimento depois dos achados da genética molecular
• Beneficiário: Rui Monteiro de Barros Maciel
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 09/11257-7 - Análise do Papel da Arginase II (ARG2) na Patogênese dos Tumores da Tiróide
• Beneficiário: Janete Maria Cerutti
• Modalidade de apoio: Auxílio à Pesquisa - Regular