High Penetrance of Pheochromocytoma Associated with the Novel C634Y/Y791F Double Germline Mutation in the RET Protooncogene

Autor(es):Mostrar menos -

Toledo, Rodrigo A. ^[1] ; Wagner, Simona M. ^[2] ; Coutinho, Flavia L. ^[1] ; Lourenco, Jr., Delmar M. ^[1] ; Azevedo, Juliana A. ^[1] ; Longuini, Viviane C. ^[1] ; Reis, Mariana T. A. ^[3] ; Siqueira, Sheila A. C. ^[4] ; Lucon, Antonio M. ^[5] ; Tavares, Marcos R. ^[6] ; Fragoso, Maria C. B. V. ^[7] ; Pereira, Adelaide A. ^[7] ; Dahia, Patricia L. M. ^[8] ; Mulligan, Lois M. ^[2] ; Toledo, Sergio P. A. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Med, Hosp Clin, Endocrine Genet Unit, Lab Invest Med 25, LIM 25, BR-01240690 Sao Paulo - Brazil

^[2] Queens Univ, Canc Res Inst, Div Canc Biol & Genet, Kingston, ON 7L 3N6 - Canada

^[3] Santa Marcelina Hosp, Endocrinol Sect, BR-08270070 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Sch Med, Hosp Clin, Div Pathol, BR-01240690 Sao Paulo - Brazil

^[5] Univ Sao Paulo, Sch Med, Hosp Clin, Dept Urol, BR-01240690 Sao Paulo - Brazil

^[6] Univ Sao Paulo, Sch Med, Hosp Clin, Dept Head & Neck Surg, BR-01240690 Sao Paulo - Brazil

^[7] Univ Sao Paulo, Sch Med, Hosp Clin, Dept Endocrinol, BR-01240690 Sao Paulo - Brazil

^[8] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Hematol & Mol Oncol, San Antonio, TX 78229 - USA

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 95, n. 3, p. 1318-1327, MAR 2010.
• Citações Web of Science: 36

Resumo

Context: Previous studies have shown that double RET mutations may be associated with unusual multiple endocrine neoplasia type 2 (MEN 2) phenotypes. Objective: Our objective was to report the clinical features of patients harboring a previously unreported double mutation of the RET gene and to characterize this mutation in vitro. Patients: Sixteen patients from four unrelated families and harboring the C634Y/Y791F double RET germline mutation were included in the study. Results: Large pheochromocytomas measuring 6.0-14 cm and weighing upto 640 g were identified in the four index cases. Three of the four tumors were bilateral. High penetrance of pheochromocytoma was also seen in the C634Y/Y791F-mutation-positive relatives (seven of nine, 77.7%). Of these, two cases had bilateral tumors, one presented with multifocal tumors, two cases had large tumors (>5 cm), and one case, which was diagnosed with a large (5.5 x 4.5 x 4.0 cm) pheochromocytoma, reported early onset of symptoms of the disease (14 yr old). The overall penetrance of pheochromocytoma was 84.6% (11 of 13). Development of medullary thyroid carcinoma in our patients seemed similar to that observed in patients with codon 634 mutations. Haplotype analysis demonstrated that the mutation did not arise from a common ancestor. In vitro studies showed the double C634Y/Y791F RET receptor was significantly more phosphorylated than either activated wild-type receptor or single C634Y and Y791F RET mutants. Conclusions: Our data suggest that the natural history of the novel C634Y/Y791F double mutation carries a codon 634-like pattern of medullary thyroid carcinoma development, is associated with increased susceptibility to unusually large bilateral pheochromocytomas, and is likely more biologically active than each individual mutation. (J Clin Endocrinol Metab 95: 1318-1327, 2010) (AU)

• Processo FAPESP: 10/07250-4 - Alta penetrância de Feocromocitoma associada à uma nova dupla mutação RET C634Y/Y791F.
• Beneficiário: Sergio Pereira de Almeida Toledo
• Modalidade de apoio: Auxílio à Pesquisa - Publicações científicas - Artigo
• Processo FAPESP: 08/58552-0 - Neoplasia endócrina múltipla tipo 1 (NEM1): análises de mutações germinativas nos genes supressores de tumor MEN1, CDKN1B/p27Kip1 e AIP; estudo de expressão gênica e proteica e; caracterização clínica
• Beneficiário: Delmar Muniz Lourenço Jr
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado