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

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.comUniversity of Texas Health Science Center at San Antonio (UTHSCSA)National Cancer Institute (NCI/NIH)[P30 CA54174]National Institute on Aging (NIA/NIH)[P30 AG013319]National Institute on Aging (NIA/NIH)[P01AG19316]Department of Microbiology, UTHSCSAFundacao Faculdade de MedicinaDivision of EndocrinologySao Paulo State Research Foundation (FAPESP)[2009/15386-6]Cancer Research UKBelgian Federal Science Policy, network[6/05]Belgian French Community Ministry[07/12-005]la Communaute Francaise de Wallonie-Bruxelles et la Lotterie NationaleFRS-FNRS (Fonds de la Recherche Scientifique), BelgiumNCI[5 P30 CA465920]Italian University and Research Ministry[2006060473]Fondazione della Comunita BrescianaCNPq Conselho Nacional de Desenvolvimento Cientifico e TecnologicoFondo de Investigaciones Sanitarias[PI 08/080883]Fundacion Mutua Madrilena[AP2775/2008]Voelcker FundAlex`s Lemonade Stand FoundationConcern FoundationNational Institutes of Health (NIH