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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Spectrum and Prevalence of FP/TMEM127 Gene Mutations in Pheochromocytomas and Paragangliomas

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Autor(es):
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Yao, Li [1, 2] ; Schiavi, Francesca [3] ; Cascon, Alberto [4, 5] ; Qin, Yuejuan [1, 2] ; Inglada-Perez, Lucia [4, 5] ; King, Elizabeth E. [1, 6] ; Toledo, Rodrigo A. [7] ; Ercolino, Tonino [8] ; Rapizzi, Elena [8] ; Ricketts, Christopher J. [9, 10] ; Mori, Luigi [11] ; Giacche, Mara [11] ; Mendola, Antonella [12] ; Taschin, Elisa [3] ; Boaretto, Francesca [3] ; Loli, Paola [13] ; Iacobone, Maurizio [14] ; Rossi, Gian-Paolo [15] ; Biondi, Bernadette [16] ; Lima-Junior, Jose Viana [17] ; Kater, Claudio E. [17] ; Bex, Marie [18] ; Vikkula, Miikka [12] ; Grossman, Ashley B. [19] ; Gruber, Stephen B. [20] ; Barontini, Marta [21] ; Persu, Alexandre [22] ; Castellano, Maurizio [11] ; Toledo, Sergio P. A. [7] ; Maher, Eamonn R. [9, 10] ; Mannelli, Massimo [8, 23] ; Opocher, Giuseppe [3, 24] ; Robledo, Mercedes [4, 5] ; Dahia, Patricia L. M. [25, 1, 2]
Número total de Autores: 34
Afiliação do(s) autor(es):
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[1] Univ Texas Hlth Sci Ctr San Antonio, Div Hematol & Med Oncol, San Antonio, TX 78229 - USA
[2] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Canc Therapy & Res Ctr, San Antonio, TX 78229 - USA
[3] Univ Padua, Veneto Inst Oncol, Familial Canc Clin, Padua - Italy
[4] Spanish Natl Canc Res Ctr, Hereditary Endocrine Canc Grp, Madrid - Spain
[5] Inst Salud Carlos III, Ctr Biomed Res Rare Dis, Madrid - Spain
[6] Univ Texas Hlth Sci Ctr San Antonio, Div Endocrinol, San Antonio, TX 78229 - USA
[7] Univ Sao Paulo, Sch Med, Dept Med, Div Endocrinol, Endocrine Genet Unit LIM 25, Sao Paulo - Brazil
[8] Univ Florence, Dept Clin Pathophysiol, Florence - Italy
[9] Univ Birmingham, Coll Med & Dent Sci, Sch Clin & Expt Med, Birmingham, W Midlands - England
[10] Univ Birmingham, Ctr Rare Dis & Personalised Med, Birmingham, W Midlands - England
[11] Univ Brescia, Endocrine & Metab Unit, Med Clin, Brescia - Italy
[12] Catholic Univ Louvain, Clin Univ St Luc, Lab Human Mol Genet, de Duve Inst, B-1200 Brussels - Belgium
[13] Osped Niguarda Ca Granda, Dept Endocrinol, Milan - Italy
[14] Univ Padua, Dept Surg & Gastroenterol Sci, Padua - Italy
[15] Univ Padua, Dept Internal Med 4, Padua - Italy
[16] Univ Naples Federico 2, Dept Clin & Mol Endocrinol & Oncol, Naples - Italy
[17] Univ Fed Sao Paulo, Dept Med, Div Endocrinol, Sao Paulo - Brazil
[18] Katholieke Univ Leuven Hosp, Dept Endocrinol, Leuven - Belgium
[19] St Bartholomews Hosp, Barts & London Sch Med, Ctr Endocrinol, London - England
[20] Univ Michigan, Div Mol Med & Genet, Ann Arbor, MI 48109 - USA
[21] Hosp Ninos Dr Ricardo Gutierrez, Ctr Invest Endocrinol, Buenos Aires, DF - Argentina
[22] Catholic Univ Louvain, Clin Univ St Luc, Div Cardiol, B-1200 Brussels - Belgium
[23] Ist Toscano Tumori, Florence - Italy
[24] Univ Padua, Dept Med & Surg Sci, Padua - Italy
[25] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 - USA
Número total de Afiliações: 25
Tipo de documento: Artigo Científico
Fonte: JAMA; v. 304, n. 23, p. 2611-2619, DEC 15 2010.
Citações Web of Science: 108
Resumo

Context Pheochromocytomas and paragangliomas are genetically heterogeneous neural crest-derived neoplasms. We recently identified germline mutations of the novel transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromocytomas consistent with a tumor suppressor effect. Objectives To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. Design, Setting, and Participants We sequenced the FP/TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without mutations in other susceptibility genes from 8 independent worldwide referral centers between January 2009 and June 2010. A multiplex polymerase chain reaction-based method was developed to screen for large gene deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant proteins was used to determine their subcellular localization. Main Outcome Measures The frequency and type of FP/TMEM127 mutation or deletion was assessed and correlated with clinical variables; the subcellular localization of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein. Results We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers had adrenal tumors, including 7 bilateral (P=2.7 x 10(-4)) and/or with familial disease (5 of 20 samples; P=.005). The median age at disease onset in the FP/TMEM127 mutation group was similar to that of patients without a mutation (41.5 vs 45 years, respectively; P=.54). The most common presentation was that of a single benign adrenal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse localization of the mutant proteins in contrast with the discrete multiorganelle distribution of wild-type TMEM127. Conclusions Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occured in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein. JAMA. 2010;304(23):2611-2619 www.jama.com (AU)

Processo FAPESP: 09/15386-6 - Análise dos genes CDKN1A, CDKN1B, CDKN2B e CDKN2C, nas Neoplasias Endócrinas Múltiplas tipo 1 e 2
Beneficiário:Rodrigo de Almeida Toledo
Linha de fomento: Bolsas no Brasil - Pós-Doutorado