Portal de Periódicos da CAPES

Artigo Acesso aberto Produção Nacional Revisado por pares

BIBTEX RIS

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

2010; American Medical Association; Volume: 304; Issue: 23 Linguagem: Inglês

10.1001/jama.2010.1830

1538-3598

Li Yao, Francesca Schiavi, Alberto Cascón, Yuejuan Qin, Lucía Inglada‐Pérez, Elizabeth E. King, Rodrigo A. Toledo, Tonino Ercolino, Elena Rapizzi, Christopher J. Ricketts, Luigi Mori, Mara Giacché, Antonella Mendola, Elisa Taschin, Francesca Boaretto, Paola Loli, Maurizio Iacobone, Gian Paolo Rossi, Bernadette Biondi, José Viana Lima-Junior, Cláudio E. Kater, Marie Bex, Miikka Vikkula, Ashley Grossman, Stephen B. Gruber, Marta Barontini, Alexandre Persu, Maurizio Castellano, S. P. A. Toledo, Eamonn R. Maher, Massimo Mannelli, Giuseppe Opocher, Mercedes Robledo, Patricia L. M. Dahia,

Cancer, Hypoxia, and Metabolism

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 × 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.