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

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

University 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, UTHSCSA

Fundacao Faculdade de Medicina

Division of Endocrinology

Sao Paulo State Research Foundation (FAPESP)[2009/15386-6]

Cancer Research UK

Belgian Federal Science Policy, network[6/05]

Belgian French Community Ministry[07/12-005]

la Communaute Francaise de Wallonie-Bruxelles et la Lotterie Nationale

FRS-FNRS (Fonds de la Recherche Scientifique), Belgium

NCI[5 P30 CA465920]

Italian University and Research Ministry[2006060473]

Fondazione della Comunita Bresciana

CNPq Conselho Nacional de Desenvolvimento Cientifico e Tecnologico

Fondo de Investigaciones Sanitarias[PI 08/080883]

Fundacion Mutua Madrilena[AP2775/2008]

Voelcker Fund

Alex`s Lemonade Stand Foundation

Concern Foundation

National Institutes of Health (NIH)