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

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dc.contributor.authorYao, Li
dc.contributor.authorSchiavi, Francesca
dc.contributor.authorCascon, Alberto
dc.contributor.authorQin, Yuejuan
dc.contributor.authorInglada-Perez, Lucia
dc.contributor.authorKing, Elizabeth E.
dc.contributor.authorToledo, Rodrigo A.
dc.contributor.authorErcolino, Tonino
dc.contributor.authorRapizzi, Elena
dc.contributor.authorRicketts, Christopher J.
dc.contributor.authorMori, Luigi
dc.contributor.authorGiacche, Mara
dc.contributor.authorMendola, Antonella
dc.contributor.authorTaschin, Elisa
dc.contributor.authorBoaretto, Francesca
dc.contributor.authorLoli, Paola
dc.contributor.authorIacobone, Maurizio
dc.contributor.authorRossi, Gian-Paolo
dc.contributor.authorBiondi, Bernadette
dc.contributor.authorLima-Junior, Jose Viana [UNIFESP]
dc.contributor.authorKater, Claudio E. [UNIFESP]
dc.contributor.authorBex, Marie
dc.contributor.authorVikkula, Miikka
dc.contributor.authorGrossman, Ashley B.
dc.contributor.authorGruber, Stephen B.
dc.contributor.authorBarontini, Marta
dc.contributor.authorPersu, Alexandre
dc.contributor.authorCastellano, Maurizio
dc.contributor.authorToledo, Sergio P. A.
dc.contributor.authorMaher, Eamonn R.
dc.contributor.authorMannelli, Massimo
dc.contributor.authorOpocher, Giuseppe
dc.contributor.authorRobledo, Mercedes
dc.contributor.authorDahia, Patricia L. M.
dc.contributor.institutionUniv Texas Hlth Sci Ctr San Antonio
dc.contributor.institutionUniv Padua
dc.contributor.institutionSpanish Natl Canc Res Ctr
dc.contributor.institutionInst Salud Carlos III
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniv Florence
dc.contributor.institutionIst Toscano Tumori
dc.contributor.institutionUniv Birmingham
dc.contributor.institutionUniv Brescia
dc.contributor.institutionCatholic Univ Louvain
dc.contributor.institutionOsped Niguarda Ca Granda
dc.contributor.institutionUniv Naples Federico 2
dc.contributor.institutionKatholieke Univ Leuven Hosp
dc.contributor.institutionSt Bartholomews Hosp
dc.contributor.institutionUniv Michigan
dc.contributor.institutionHosp Ninos Dr Ricardo Gutierrez
dc.date.accessioned2016-01-24T14:05:48Z
dc.date.available2016-01-24T14:05:48Z
dc.date.issued2010-12-15
dc.description.abstractContext 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.comen
dc.description.affiliationUniv Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA
dc.description.affiliationUniv Texas Hlth Sci Ctr San Antonio, Div Hematol & Med Oncol, San Antonio, TX 78229 USA
dc.description.affiliationUniv Texas Hlth Sci Ctr San Antonio, Div Endocrinol, San Antonio, TX 78229 USA
dc.description.affiliationUniv Texas Hlth Sci Ctr San Antonio, Dept Med, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA
dc.description.affiliationUniv Padua, Veneto Inst Oncol, Familial Canc Clin, Padua, Italy
dc.description.affiliationUniv Padua, Dept Surg & Gastroenterol Sci, Padua, Italy
dc.description.affiliationUniv Padua, Dept Internal Med 4, Padua, Italy
dc.description.affiliationUniv Padua, Dept Med & Surg Sci, Padua, Italy
dc.description.affiliationSpanish Natl Canc Res Ctr, Hereditary Endocrine Canc Grp, Madrid, Spain
dc.description.affiliationInst Salud Carlos III, Ctr Biomed Res Rare Dis, Madrid, Spain
dc.description.affiliationUniv São Paulo, Sch Med, Dept Med, Div Endocrinol,Endocrine Genet Unit LIM 25, São Paulo, Brazil
dc.description.affiliationUniversidade Federal de São Paulo, Dept Med, Div Endocrinol, São Paulo, Brazil
dc.description.affiliationUniv Florence, Dept Clin Pathophysiol, Florence, Italy
dc.description.affiliationIst Toscano Tumori, Florence, Italy
dc.description.affiliationUniv Birmingham, Coll Med & Dent Sci, Sch Clin & Expt Med, Birmingham, W Midlands, England
dc.description.affiliationUniv Birmingham, Ctr Rare Dis & Personalised Med, Birmingham, W Midlands, England
dc.description.affiliationUniv Brescia, Endocrine & Metab Unit, Med Clin, Brescia, Italy
dc.description.affiliationCatholic Univ Louvain, Clin Univ St Luc, Lab Human Mol Genet, de Duve Inst, B-1200 Brussels, Belgium
dc.description.affiliationCatholic Univ Louvain, Clin Univ St Luc, Div Cardiol, B-1200 Brussels, Belgium
dc.description.affiliationOsped Niguarda Ca Granda, Dept Endocrinol, Milan, Italy
dc.description.affiliationUniv Naples Federico 2, Dept Clin & Mol Endocrinol & Oncol, Naples, Italy
dc.description.affiliationKatholieke Univ Leuven Hosp, Dept Endocrinol, Leuven, Belgium
dc.description.affiliationSt Bartholomews Hosp, Barts & London Sch Med, Ctr Endocrinol, London, England
dc.description.affiliationUniv Michigan, Div Mol Med & Genet, Ann Arbor, MI 48109 USA
dc.description.affiliationHosp Ninos Dr Ricardo Gutierrez, Ctr Invest Endocrinol, Buenos Aires, DF, Argentina
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Med, Div Endocrinol, São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipUniversity of Texas Health Science Center at San Antonio (UTHSCSA)
dc.description.sponsorshipNational Cancer Institute (NCI)
dc.description.sponsorshipNational Institute on Aging (NIA)
dc.description.sponsorshipDepartment of Microbiology, UTHSCSA
dc.description.sponsorshipFundacao Faculdade de Medicina
dc.description.sponsorshipDivision of Endocrinology
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipCancer Research UK
dc.description.sponsorshipBelgian Federal Science Policy, network
dc.description.sponsorshipBelgian French Community Ministry
dc.description.sponsorshipla Communaute Francaise de Wallonie-Bruxelles et la Lotterie Nationale
dc.description.sponsorshipFRS-FNRS (Fonds de la Recherche Scientifique), Belgium
dc.description.sponsorshipNCI
dc.description.sponsorshipItalian University and Research Ministry
dc.description.sponsorshipFondazione della Comunita Bresciana
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipFondo de Investigaciones Sanitarias
dc.description.sponsorshipFundacion Mutua Madrilena
dc.description.sponsorshipVoelcker Fund
dc.description.sponsorshipAlex's Lemonade Stand Foundation
dc.description.sponsorshipConcern Foundation
dc.description.sponsorshipNational Institutes of Health
dc.description.sponsorshipIDNational Cancer Institute (NCI): P30 CA54174
dc.description.sponsorshipIDNational Institute on Aging (NIA): P30 AG013319
dc.description.sponsorshipIDNational Institute on Aging (NIA): P01AG19316
dc.description.sponsorshipIDFAPESP: 2009/15386-6
dc.description.sponsorshipIDBelgian Federal Science Policy, network: 6/05
dc.description.sponsorshipIDBelgian French Community Ministry: 07/12-005
dc.description.sponsorshipIDNCI: 5 P30 CA465920
dc.description.sponsorshipIDItalian University and Research Ministry: 2006060473
dc.description.sponsorshipIDFondo de Investigaciones Sanitarias: PI 08/080883
dc.description.sponsorshipIDFundacion Mutua Madrilena: AP2775/2008
dc.format.extent2611-2619
dc.identifierhttp://dx.doi.org/10.1001/jama.2010.1830
dc.identifier.citationJama-Journal of the American Medical Association. Chicago: Amer Medical Assoc, v. 304, n. 23, p. 2611-2619, 2010.
dc.identifier.doi10.1001/jama.2010.1830
dc.identifier.issn0098-7484
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/33168
dc.identifier.wosWOS:000285303400024
dc.language.isoeng
dc.publisherAmer Medical Assoc
dc.relation.ispartofJama-Journal of the American Medical Association
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.titleSpectrum and Prevalence of FP/TMEM127 Gene Mutations in Pheochromocytomas and Paragangliomasen
dc.typeinfo:eu-repo/semantics/article
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