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

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

Author Yao, Li Google Scholar
Schiavi, Francesca Google Scholar
Cascon, Alberto Google Scholar
Qin, Yuejuan Google Scholar
Inglada-Perez, Lucia Google Scholar
King, Elizabeth E. Google Scholar
Toledo, Rodrigo A. Google Scholar
Ercolino, Tonino Google Scholar
Rapizzi, Elena Google Scholar
Ricketts, Christopher J. Google Scholar
Mori, Luigi Google Scholar
Giacche, Mara Google Scholar
Mendola, Antonella Google Scholar
Taschin, Elisa Google Scholar
Boaretto, Francesca Google Scholar
Loli, Paola Google Scholar
Iacobone, Maurizio Google Scholar
Rossi, Gian-Paolo Google Scholar
Biondi, Bernadette Google Scholar
Lima-Junior, Jose Viana Autor UNIFESP Google Scholar
Kater, Claudio E. Autor UNIFESP Google Scholar
Bex, Marie Google Scholar
Vikkula, Miikka Google Scholar
Grossman, Ashley B. Google Scholar
Gruber, Stephen B. Google Scholar
Barontini, Marta Google Scholar
Persu, Alexandre Google Scholar
Castellano, Maurizio Google Scholar
Toledo, Sergio P. A. Google Scholar
Maher, Eamonn R. Google Scholar
Mannelli, Massimo Google Scholar
Opocher, Giuseppe Google Scholar
Robledo, Mercedes Google Scholar
Dahia, Patricia L. M. Google Scholar
Institution Univ Texas Hlth Sci Ctr San Antonio
Univ Padua
Spanish Natl Canc Res Ctr
Inst Salud Carlos III
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Univ Florence
Ist Toscano Tumori
Univ Birmingham
Univ Brescia
Catholic Univ Louvain
Osped Niguarda Ca Granda
Univ Naples Federico 2
Katholieke Univ Leuven Hosp
St Bartholomews Hosp
Univ Michigan
Hosp Ninos Dr Ricardo Gutierrez
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
Language English
Sponsor University of Texas Health Science Center at San Antonio (UTHSCSA)
National Cancer Institute (NCI)
National Institute on Aging (NIA)
Department of Microbiology, UTHSCSA
Fundacao Faculdade de Medicina
Division of Endocrinology
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Cancer Research UK
Belgian Federal Science Policy, network
Belgian French Community Ministry
la Communaute Francaise de Wallonie-Bruxelles et la Lotterie Nationale
FRS-FNRS (Fonds de la Recherche Scientifique), Belgium
Italian University and Research Ministry
Fondazione della Comunita Bresciana
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Fondo de Investigaciones Sanitarias
Fundacion Mutua Madrilena
Voelcker Fund
Alex's Lemonade Stand Foundation
Concern Foundation
National Institutes of Health
Grant number National Cancer Institute (NCI): P30 CA54174
National Institute on Aging (NIA): P30 AG013319
National Institute on Aging (NIA): P01AG19316
FAPESP: 2009/15386-6
Belgian Federal Science Policy, network: 6/05
Belgian French Community Ministry: 07/12-005
NCI: 5 P30 CA465920
Italian University and Research Ministry: 2006060473
Fondo de Investigaciones Sanitarias: PI 08/080883
Fundacion Mutua Madrilena: AP2775/2008
Date 2010-12-15
Published in Jama-Journal of the American Medical Association. Chicago: Amer Medical Assoc, v. 304, n. 23, p. 2611-2619, 2010.
ISSN 0098-7484 (Sherpa/Romeo, impact factor)
Publisher Amer Medical Assoc
Extent 2611-2619
Origin http://dx.doi.org/10.1001/jama.2010.1830
Access rights Closed access
Type Article
Web of Science ID WOS:000285303400024
URI http://repositorio.unifesp.br/handle/11600/33168

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