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

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Spectrum and Prevalence of FP/TMEM127 Gene Mutations in Pheochromocytomas and Paragangliomas ORIGINAL CONTRIBUTION Spectrum and Prevalence of FP/TMEM127 Gene Mutations in Pheochromocytomas and Paragangliomas Li Yao, PhD Context Pheochromocytomas and paragangliomas are genetically heterogeneous neu- Francesca Schiavi, MD, PhD ral crest–derived neoplasms. We recently identified germline mutations of the novel Alberto Cascon, PhD transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromo- cytomas consistent with a tumor suppressor effect. Yuejuan Qin, MD, PhD Objectives To examine the prevalence and spectrum of FP/TMEM127 mutations Lucia Inglada-Pe´rez, PhD in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. Elizabeth E. King, MD Design, Setting, and Participants We sequenced the FP/TMEM127 gene in 990 Rodrigo A. Toledo, PhD individuals with pheochromocytomas and/or paragangliomas, including 898 previ- ously unreported cases without mutations in other susceptibility genes from 8 inde- Tonino Ercolino, PhD pendent worldwide referral centers between January 2009 and June 2010. A multi- Elena Rapizzi, PhD plex polymerase chain reaction–based method was developed to screen for large gene Christopher J. Ricketts, PhD deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant pro- teins was used to determine their subcellular localization. Luigi Mori, PhD Main Outcome Measures The frequency and type of FP/TMEM127 mutation or Mara Giacchè, PhD deletion was assessed and correlated with clinical variables; the subcellular localization Antonella Mendola, PhD of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein. Elisa Taschin, PhD Results We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers Francesca Boaretto, PhD had adrenal tumors, including 7 bilateral (P=2.7ϫ10−4) and/or with familial disease Paola Loli, MD (5 of 20 samples; P=.005). The median age at disease onset in the FP/TMEM127 mu- tation group was similar to that of patients without a mutation (41.5 vs 45 years, re- Maurizio Iacobone, MD spectively; P=.54). The most common presentation was that of a single benign ad- Gian-Paolo Rossi, MD renal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier Bernadette Biondi, MD (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse lo- calization of the mutant proteins in contrast with the discrete multiorganelle distribu- Jose´ Viana Lima-Junior, MD tion of wild-type TMEM127. Claudio E. Kater, MD Conclusions Germline mutations of FP/TMEM127 were associated with pheochro- Marie Bex, MD mocytoma but not paraganglioma and occured in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular Miikka Vikkula, PhD distribution of the FP/TMEM127 protein. Ashley B. Grossman, MD JAMA. 2010;304(23):2611-2619 www.jama.com Stephen B. Gruber, MD Marta Barontini, MD HEOCHROMOCYTOMAS AND geneous, with at least one-third of paragangliomas are chromaf- cases resulting from germline but not Alexandre Persu, MD fin cell tumors of neural crest somatic mutations in 1 of several Maurizio Castellano, MD origin that arise from the independent genes: RET, VHL, NF1, Padrenal medulla or extra-adrenal sym- and succinate dehydrogenase (SDH) Sergio P. A. Toledo, MD 2-5 Eamonn R. Maher, MD, FMedSci pathetic paraganglia, respectively, and subunit B, C, and D genes. More are frequently catecholamine secret- recently, other candidate susceptibil- Massimo Mannelli, MD ing.1 These tumors are usually benign Giuseppe Opocher, MD and can occur as a single entity or as Author Affiliations are listed at the end of this article. Mercedes Robledo, PhD part of various hereditary tumor syn- Corresponding Author: Patricia L. M. Dahia, MD, PhD, dromes. Genetically, pheochromocy- Department of Cellular and Structural Biology, Uni- Patricia L. M. Dahia, MD, PhD versity of Texas Health Science Center at San Anto- tomas and paragangliomas are hetero- nio, San Antonio, TX 78229 ([email protected]). ©2010 American Medical Association. All rights reserved. (Reprinted with Corrections) JAMA, December 15, 2010—Vol 304, No. 23 2611 Downloaded From: https://jamanetwork.com/ on 09/26/2021 MUTATIONS IN PHEOCHROMOCYTOMAS AND PARAGANGLIOMAS ity genes have also been reported, mined the subcellular localization of 5 tations in other known pheochromocy- including KIF1Bβ,6,7 EgIN1/PHD2,8 novel mutations by in vitro confocal toma susceptibility genes were ex- SDHAF2,9,10 and SDHA,11 although microscopy. cluded.14 The main features of each series these findings remain restricted to 1 of the entire cohort are shown in TABLE 1. or 2 occurrences of the reported METHODS mutations. Despite this broad spec- Patients DNA Isolation trum of susceptibility genes, the A total of 990 samples from patients with Of the new series of 898 samples, DNA molecular basis for the majority of pheochromocytomas and paraganglio- was isolated from blood in 774 cases pheochromocytomas and paraganglio- mas without mutations in RET, VHL, and from tumor tissue in 124 cases, fol- mas, including most of the sporadic SDHB, SDHC, and SDHD and who had lowing standard procedures.14 and rare familial cases, remains no clinical features of neurofibromato- unknown. These observations support sis type 1 were studied. In addition, 319 Control Population the existence of additional pheochro- of these samples were negative for A control group composed of samples of mocytoma susceptibility genes, which SDHAF2 and 52 for KIF1Bβ gene muta- Europeans, South Americans (heteroge- may account for some of the geneti- tions. A cohort of 898 samples were re- neous population mainly of Latino ori- cally undefined cases.12,13 cruited from a multi-institutional col- gin but also including non-Hispanic We recently identified TMEM12714 laborative effort derived from the whites, Asians, African Americans, and (NM_017849.3) as the pathogenic tar- International Familial Pheochromocy- indigenous Native Americans), North get of the familial pheochromocytoma toma Consortium, which encompassed Americans (including both Hispanic and (FP) locus, which we previously mapped referral centers based in the United States non-Hispanic whites and African Ameri- to chromosome 2q11.13 Germline (San Antonio, Texas, and Ann Arbor, cans), and Asians totaling 1064 alleles FP/TMEM127 mutations were found Michigan), Italy (Padova, Florence, and was used as reference samples, as re- both in familial and sporadic-appear- Brescia), Spain (Madrid), England (Bir- ported.14 In addition to these, 718 new ing pheochromocytomas, with loss of mingham and London), Brazil (Sa˜o alleles were screened for exon 3 of the the wild-type allele in tumor DNA con- Paulo), Belgium (Brussels), and Argen- FP/TMEM127 gene only. This group sistent with its role as a tumor suppres- tina (Buenos Aires). Written informed comprised 318 alleles of white ancestry sor gene. FP/TMEM127 encodes a highly consent was obtained from patients in ac- and 404 alleles of South American ori- conserved 3-spanner transmembrane cordance with institutional review gin similar in racial/ethnic composition protein that localizes to multiple intra- board–approved protocols from each to those described above. cellular organelles and is linked to regu- center. Eighteen samples were ob- lation of the mTORC1 signaling com- tained from the Cancer Therapy and Re- Polymerase Chain Reaction plex, a critical control node for protein search Center Pathology Tumor Bank at and Direct Sequencing synthesis and cell survival.14 All but 1 the University of Texas Health Science To define the prevalence of FP/TMEM127 of the 7 initially discovered mutations Center at San Antonio. Diagnosis of mutationinalarge,multi-institutionalco- were truncating and resulted in mark- pheochromocytoma and/or paragan- hortofpheochromocytomasandparagan- edly reduced expression of the glioma, including tumors of both sym- gliomas,all4exonsofFP/TMEM127were FP/TMEM127 gene in the evaluable tu- pathetic (thoracic or abdominal) and amplified by polymerase chain reaction mors, suggesting that the mutations re- parasympathetic (head and neck) ori- (PCR) and directly sequenced as previ- sult in loss of FP/TMEM127 function in gin, was established following conven- ously reported.14 Primer sequences the tumor tissue. tional procedures (including clinical, bio- are listed in eTable 1 (available at http: In recent years, specific genotype- chemical, and imaging tests) and the //www.jama.com). phenotype associations in pheochromo- diagnosis was confirmed histologically The accession numbers for nucleo- cytomas due to mutations in the vari- in every case. Tumors were considered tides (NM_017849.3) and respective ous susceptibility genes have spurred the familial when more than 1 affected in- protein variations (NP_060319.1) de- development of guidelines for genetic dividual was identified in the family. The tected in this study were deposited in screening of these patients, with a goal study was performed between January the National Center for Biotechnology of improving the outcomes of affected 2009 and June 2010. Information (NCBI) single-nucleotide and at-risk individuals.3,5,15,16 To define We previously reported FP/TMEM127 polymorphism (SNP) database (http: the prevalence and genotype-pheno- sequence variations in a cohort of 103 //www.ncbi.nlm.nih.gov/SNP/tranSNP type correlations in FP/TMEM127- patients with pheochromocytoma and/or /VarBatchSub.cgi). mutated cases,
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