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

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

• Document type: Journal article
• Source: JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; v. 304, n. 23, p. 9-pg., 2010-12-15.

Abstract

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)

• FAPESP's process: 09/15386-6 - Analysis of the CDKN1A, CDKN1B, CDKN2B and CDKN2C genes in multiple endocrine neoplasias type 1 and 2.
• Grantee: Rodrigo de Almeida Toledo
• Support Opportunities: Scholarships in Brazil - Post-Doctoral