Gene Summary

Gene:TMEM127; transmembrane protein 127
Summary:This gene encodes a transmembrane protein with 3 predicted transmembrane domains. The protein is associated with a subpopulation of vesicular organelles corresponding to early endosomal structures, with the Golgi, and with lysosomes, and may participate in protein trafficking between these structures. Mutations in this gene and several other genes cause pheochromocytomas. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Aug 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transmembrane protein 127
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Latest Publications: TMEM127 (cancer-related)

Deng Y, Qin Y, Srikantan S, et al.
The TMEM127 human tumor suppressor is a component of the mTORC1 lysosomal nutrient-sensing complex.
Hum Mol Genet. 2018; 27(10):1794-1808 [PubMed] Free Access to Full Article Related Publications
The TMEM127 tumor suppressor gene encodes a transmembrane protein of unknown function mutated in pheochromocytomas and, rarely, in renal cancers. Tumors with inactivating TMEM127 mutations have increased mTORC1 signaling by undefined mechanisms. Here we report that TMEM127 interacts with the lysosome-anchored complex comprised of Rag GTPases, the LAMTOR pentamer (or 'ragulator') and vATPase, which controls amino acid-mediated mTORC1 activation. We found that under nutrient-rich conditions TMEM127 expression reduces mTORC1 recruitment to Rags. In addition, TMEM127 interacts with LAMTOR in an amino acid-dependent manner and decreases the LAMTOR1-vATPase association, while TMEM127-vATPase binding requires intact lysosomal acidification but is amino acid independent. Conversely, both murine and human cells lacking TMEM127 accumulate LAMTOR proteins in the lysosome. Consistent with these findings, pheochromocytomas with TMEM127 mutations have increased levels of LAMTOR proteins. These results suggest that TMEM127 interactions with ragulator and vATPase at the lysosome contribute to restrain mTORC1 signaling in response to amino acids, thus explaining the increased mTORC1 activation seen in TMEM127-deficient tumors.

Lussey-Lepoutre C, Buffet A, Morin A, et al.
Rodent models of pheochromocytoma, parallels in rodent and human tumorigenesis.
Cell Tissue Res. 2018; 372(2):379-392 [PubMed] Related Publications
Paragangliomas and pheochromocytomas are rare neuroendocrine tumors characterized by a large spectrum of hereditary predisposition. Based on gene expression profiling classification, they can be classically assigned to either a hypoxic/angiogenic cluster (cluster 1 including tumors with mutations in SDHx, VHL and FH genes) or a kinase-signaling cluster (cluster 2 consisting in tumors related to RET, NF1, TMEM127 and MAX genes mutations, as well as most of the sporadic tumors). The past 15 years have seen the emergence of an increasing number of genetically engineered and grafted models to investigate tumorigenesis and develop new therapeutic strategies. Among them, only cluster 2-related predisposed models have been successful but grafted models are however available to study cluster 1-related tumors. In this review, we present an overview of existing rodent models targeting predisposition genes involved or not in human pheochromocytoma/paraganglioma susceptibility and their contribution to the improvement of pheochromocytoma experimental research.

Casey RT, Warren AY, Martin JE, et al.
Clinical and Molecular Features of Renal and Pheochromocytoma/Paraganglioma Tumor Association Syndrome (RAPTAS): Case Series and Literature Review.
J Clin Endocrinol Metab. 2017; 102(11):4013-4022 [PubMed] Free Access to Full Article Related Publications
Context: The co-occurrence of pheochromocytoma (PC) and renal tumors was linked to the inherited familial cancer syndrome von Hippel-Lindau (VHL) disease more than six decades ago. Subsequently, other shared genetic causes of predisposition to renal tumors and to PC, paraganglioma (PGL), or head and neck paraganglioma (HNPGL) have been described, but case series of non-VHL-related cases of renal tumor and pheochromocytoma/paraganglioma tumor association syndrome (RAPTAS) are rare.
Objective: To determine the clinical and molecular features of non-VHL RAPTAS by literature review and characterization of a case series.
Design: A review of the literature was performed and a retrospective study of referrals for investigation of genetic causes of RAPTAS.
Results: Literature review revealed evidence of an association, in addition to VHL disease, between germline mutations in SDHB, SDHC, SDHD, TMEM127, and MAX genes and RAPTAS [defined here as the co-occurrence of tumors from both classes (PC/PGL/HNPGL and renal tumors) in the same individual or in first-degree relatives]. In both the literature review and our case series of 22 probands with non-VHL RAPTAS, SDHB mutations were the most frequent cause of non-VHL RAPTAS. A genetic cause was identified in 36.3% (8/22) of kindreds.
Conclusion: Renal tumors and PC/PGL/HNPGL tumors share common molecular features and their co-occurrence in an individual or family should prompt genetic investigations. We report a case of MAX-associated renal cell carcinoma and confirm the role of TMEM127 mutations with renal cell carcinoma predisposition.

Rednam SP, Erez A, Druker H, et al.
Von Hippel-Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood.
Clin Cancer Res. 2017; 23(12):e68-e75 [PubMed] Related Publications
Von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. We propose a new vHL screening paradigm similar to existing approaches, with important modifications for some tumor types, placing an emphasis on risks in childhood. This includes advancement in the timing of surveillance initiation and increased frequency of screening evaluations. Another neuroendocrine-related familial condition is the rapidly expanding hereditary paraganglioma and pheochromocytoma syndrome (HPP). The tumor spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumors. The majority of patients with HPP syndrome harbor an underlying variant in one of the

Sbardella E, Cranston T, Isidori AM, et al.
Routine genetic screening with a multi-gene panel in patients with pheochromocytomas.
Endocrine. 2018; 59(1):175-182 [PubMed] Related Publications
PURPOSE: Several new gene mutations have been reported in recent years to be associated with a risk of familial pheochromocytoma. However, it is unclear as to whether extensive genetic testing is required in all patients.
METHODS: The clinical data of consecutive patients operated for pheochromocytoma over a decade in a tertiary referral center were reviewed. Genetic screening was performed using a 10-gene panel: RET, VHL, SDHB, SDHD, SDHA, SDHC, SDHAF2, MAX, TMEM127 and FH.
RESULTS: A total of 166 patients were analyzed: 87 of them had genetic screening performed (39 M: 44.8%, 48 F: 55.2%, age range 6-81 years, mean 45±16.8 years). In total, 22/87 (25.3%) patients had germline mutations, while 65/87 (74.7%) patients presented with apparently sporadic tumors. Germline VHL mutations were identified in 11.7% of patients, RET in 6.8% (five MEN2A/MEN2 and one MEN2B/MEN3), SDHD in 2.3%, MAX in 2.3%, SDHB in 1.1%, and TMEM127 in 1.1% of patients. At diagnosis, 15.1% of patients with unilateral non-syndromic pheochromocytoma showed germline mutations. We identified 19.7% of mutations in patients with unilateral-non-recurrent pheochromocytomas within 5 years vs. 50% in the recurrent-bilateral-metastatic group (p = 0.01). Germline mutations were more frequently seen with bilateral pheochromocytomas (p = 0.001): 80% of patients with bilateral disease had germline mutations (4 VHL, 3 RET, 1 MAX).
CONCLUSIONS: The advent of rapid genetic screening using a gene-panel makes it feasible to screen large cohorts of patients and provides a valuable tool to contribute to the prediction of bilateral and malignant disease and to screen family members.

Bausch B, Schiavi F, Ni Y, et al.
Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.
JAMA Oncol. 2017; 3(9):1204-1212 [PubMed] Free Access to Full Article Related Publications
Importance: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking.
Objective: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes.
Design, Setting, and Patients: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes.
Main Outcomes and Measures: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized.
Results: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001).
Conclusions and Relevance: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

Gupta G, Pacak K,
Endocr Pract. 2017; 23(6):690-704 [PubMed] Related Publications
OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors known to produce and secrete high levels of circulating catecholamines and their metabolites. The biochemical characteristics of these tumors can be used to divide them into three major phenotypes. The adrenergic, noradrenergic and dopaminergic phenotypes are defined by predominant elevations in epinephrine and metanephrine, norepinephrine and normetanephrine, and dopamine and 3-methoxytyramine, respectively. There are over 15 well-identified tumor-susceptibility genes responsible for approximately 40% of the cases. The objective of this review article is to outline specific genotype/biochemical phenotype relationships.
METHODS: Literature review.
CONCLUSION: Biochemical phenotype of PPGL is determined by the underlying genetic mutation and the associated molecular pathway. Identification of genotype/biochemical relationships is valuable in prioritizing testing for specific genes, making treatment decisions and monitoring disease progression.
ABBREVIATIONS: 3-MT = 3-methoxytyramine; EPAS1 = endothelial pas domain protein 1; FH = fumarate hydratase; HIF2A = hypoxia inducible factor type 2A; MEN2 = multiple endocrine neoplasia type 2; NF1 = neurofibromatosis type 1; PNMT = phenylethanolamine N-methyltransferase; PPGL = pheochromocytoma and paraganglioma; RET = rearranged during transfection; SDH = succinate dehydrogenase; SDHAF2 = succinate dehydrogenase complex assembly factor 2; TCA = tricarboxylic acid; TH = tyrosine hydroxylase; TMEM127 = transmembrane protein 127; VHL = von Hippel-Lindau.

Pillai S, Gopalan V, Lo CY, et al.
Silent genetic alterations identified by targeted next-generation sequencing in pheochromocytoma/paraganglioma: A clinicopathological correlations.
Exp Mol Pathol. 2017; 102(1):41-46 [PubMed] Related Publications
AIMS: The goal of this pilot study was to develop a customized, cost-effective amplicon panel (Ampliseq) for target sequencing in a cohort of patients with sporadic phaeochromocytoma/paraganglioma.
METHODS: Phaeochromocytoma/paragangliomas from 25 patients were analysed by targeted next-generation sequencing approach using an Ion Torrent PGM instrument. Primers for 15 target genes (NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, MEN1, KIF1Bβ, EPAS1, CDKN2 & PHD2) were designed using ion ampliseq designer. Ion Reporter software and Ingenuity® Variant Analysis™ software ( from Ingenuity Systems were used to analysis these results.
RESULTS: Overall, 713 variants were identified. The variants identified from the Ion Reporter ranged from 64 to 161 per patient. Single nucleotide variants (SNV) were the most common. Further annotation with the help of Ingenuity variant analysis revealed 29 of these 713variants were deletions. Of these, six variants were non-pathogenic and four were likely to be pathogenic. The remaining 19 variants were of uncertain significance. The most frequently altered gene in the cohort was KIF1B followed by NF1. Novel KIF1B pathogenic variant c.3375+1G>A was identified. The mutation was noted in a patient with clinically confirmed neurofibromatosis. Chromosome 1 showed the presence of maximum number of variants.
CONCLUSIONS: Use of targeted next-generation sequencing is a sensitive method for the detecting genetic changes in patients with phaeochromocytoma/paraganglioma. The precise detection of these genetic changes helps in understanding the pathogenesis of these tumours.

Murakoshi M, Takasawa K, Nishioka M, et al.
Abdominal paraganglioma in a young woman with 1p36 deletion syndrome.
Am J Med Genet A. 2017; 173(2):495-500 [PubMed] Related Publications
1p36 deletion syndrome is the most common terminal deletion syndrome, and the genomic regions that contribute to specific 1p36 deletion syndrome-related phenotypes were recently identified. Deletions in the 1p36 region have been documented in various tumor tissues, which indicates correlation between loss of heterozygosity of 1p36 and tumor development, and the existence of tumor suppressors in this region. Therefore, it was suspected that patients with 1p36 deletion syndrome have a higher risk of tumor development; however, only a few child cases of neuroblastoma with 1p36 deletion syndrome have been reported. We report the first case of 1p36 deletion syndrome with paraganglioma (PGL) and include genetic investigation. The 24-year-old woman with 1p36 deletion syndrome had severe intellectual disability, dilated cardiomyopathy, and distinct dysmorphic features, and presented with persistent vomiting accompanied by hypertension (178/115 mmHg). Abdominal CT revealed a 40 × 50 mm retroperitoneal mass and substantial elevations of plasma and urine norepinephrine (15.4 nmol/L and 1022 µmol/mol creatinine, respectively); abnormal uptake of

Patócs A, Lendvai NK, Butz H, et al.
Novel SDHB and TMEM127 Mutations in Patients with Pheochromocytoma/Paraganglioma Syndrome.
Pathol Oncol Res. 2016; 22(4):673-9 [PubMed] Related Publications
Pheochromocytomas (Pheo) and paragangliomas (PGL) are rare tumors, with heterogeneous genetic background. In up to 30 % of all, apparently sporadic Pheo/PGL cases germline mutations can be identified in one of the 15 genes representing genetic susceptibility for Pheo/PGL. Malignancy is rare but it frequently associates with SDHB mutations. Our aim was to determine the prevalence of germline SDHx, SDHAF2, MAX and TMEM127 mutations in Hungarian patients with apparently sporadic Pheo/PGLs. Mutation screening of the SDHx, SDHAF2, MAX and TMEM127 genes was performed in 82 Hungarian patients with apparently sporadic Pheo/PGL using PCR and bidirectional Sanger sequencing. Disease-causing germline mutations were identified in 11 patients, of which 4 SDHB and 2 TMEM127 mutations were novel. Earlier development of Pheo/PGL, more malignant phenotype and multiple tumors were observed in genetically positive cases especially in those with SDHB mutations. The presence of bilateral or multiple tumors was the most predictive for identification of a pathogenic mutation. Together with cases harboring germline RET, VHL and NF1 mutations, Hungarian patients with Pheo/PGL exhibit a heterogeneous mutation spectrum, indicating that all of the Pheo/PGL susceptibility genes should be tested. Novel genotype-phenotype associations revealed by our study may contribute to improvement of diagnostic approaches and may help to achieve a better clinical follow up for patients with Pheo/PGL.

Pillai S, Gopalan V, Smith RA, Lam AK
Updates on the genetics and the clinical impacts on phaeochromocytoma and paraganglioma in the new era.
Crit Rev Oncol Hematol. 2016; 100:190-208 [PubMed] Related Publications
Genetic mutations of phaeochromocytoma (PCC) and paraganglioma (PGL) are mainly classified into two major clusters. Cluster 1 mutations are involved with the pseudo hypoxic pathway and comprised of PHD2, VHL, SDHx, IDH, HIF2A, MDH2 and FH mutated PCC/PGL. Cluster 2 mutations are associated with abnormal activation of kinase signalling pathways and included mutations of RET, NF1, KIF1Bβ, MAX and TMEM127. In addition, VHL, SDHx (cluster 1 genes) and RET, NF1 (cluster 2 genes) germline mutations are involved in the neuronal precursor cell pathway in the pathogeneses of PCC/PGL. Also, GDNF, H-ras, K-ras, GNAS, CDKN2A (p16), p53, BAP1, BRCA1&2, ATRX and KMT2D mutations have roles in the development of PCC/PGLs. Overall, known genetic mutations account for the pathogenesis of approximately 60% of PCC/PGLs. Genetic mutations, pathological parameters and biochemical markers are used for better prediction of the outcome of patients with this group of tumours. Immunohistochemistry and gene sequencing can ensure a more effective detection, prediction of malignant potential and treatment of PCC/PCLs.

Flynn A, Dwight T, Harris J, et al.
Pheo-Type: A Diagnostic Gene-expression Assay for the Classification of Pheochromocytoma and Paraganglioma.
J Clin Endocrinol Metab. 2016; 101(3):1034-43 [PubMed] Related Publications
CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are heritable neoplasms that can be classified into gene-expression subtypes corresponding to their underlying specific genetic drivers.
OBJECTIVE: This study aimed to develop a diagnostic and research tool (Pheo-type) capable of classifying PPGL tumors into gene-expression subtypes that could be used to guide and interpret genetic testing, determine surveillance programs, and aid in elucidation of PPGL biology.
DESIGN: A compendium of published microarray data representing 205 PPGL tumors was used for the selection of subtype-specific genes that were then translated to the Nanostring gene-expression platform. A support vector machine was trained on the microarray dataset and then tested on an independent Nanostring dataset representing 38 familial and sporadic cases of PPGL of known genotype (RET, NF1, TMEM127, MAX, HRAS, VHL, and SDHx). Different classifier models involving between three and six subtypes were compared for their discrimination potential.
RESULTS: A gene set of 46 genes and six endogenous controls was selected representing six known PPGL subtypes; RTK1-3 (RET, NF1, TMEM127, and HRAS), MAX-like, VHL, and SDHx. Of 38 test cases, 34 (90%) were correctly predicted to six subtypes based on the known genotype to gene-expression subtype association. Removal of the RTK2 subtype from training, characterized by an admixture of tumor and normal adrenal cortex, improved the classification accuracy (35/38). Consolidation of RTK and pseudohypoxic PPGL subtypes to four- and then three-class architectures improved the classification accuracy for clinical application.
CONCLUSIONS: The Pheo-type gene-expression assay is a reliable method for predicting PPGL genotype using routine diagnostic tumor samples.

Scollo C, Russo M, De Gregorio L, et al.
A novel RET gene mutation in a patient with apparently sporadic pheochromocytoma.
Endocr J. 2016; 63(1):87-91 [PubMed] Related Publications
Pheochromocytoma (Pheo) is a chromaffin tumor arising from the adrenal medulla. The recent discovery of new germline mutations in RET, SDHA, SDHB, SDHC, SDHD, VHL, NF1, TMEM127, MAX genes, increased the rate of genetic disease from 10% to 28% in patients with apparently sporadic tumor. RET germline mutations cause multiple endocrine neoplasia type 2 syndrome (MEN 2A) characterized by complete penetrance of medullary thyroid cancer (MTC), and lower prevalence of Pheo and hyperparathyroidism. We describe the genetic etiology of an apparently sporadic case of monolateral Pheo in a 42-year-old male patient. A new (not previously reported) MEN 2A-associated germline RET mutation located in exon 11 (Glu632Gly, caused by an A>G point mutation at position 1895 of the RET cDNA) was found in the patient but not in his living first-degree relatives. This observation increases the number of possible germline RET mutations. Genotype-phenotype correlation of this new genetic alteration is unknown, but this rare mutation is probably associated with a low risk for MTC (usually the first tumor diagnosed in MEN 2A syndrome) and with the development of Pheo before the onset of MTC. Since we expect MTC to occur in our patient, strict follow-up is mandatory. Our findings emphasize the relevance of genetic testing in patients with Pheo, especially when the clinical presentation (family history, young age at diagnosis, multiple locations, malignant lesions, and bilateralism) is suggestive.

Currás-Freixes M, Inglada-Pérez L, Mancikova V, et al.
Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients.
J Med Genet. 2015; 52(10):647-56 [PubMed] Related Publications
BACKGROUND: Nowadays, 65-80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source.
METHODS: The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL, the SDH genes, TMEM127, MAX and FH. 99 tumours from patients negative for germline screening were available and tested for RET, VHL, HRAS, EPAS1, MAX and SDHB.
RESULTS: Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p=6.62×10(-10)). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p=0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p=2.0×10(-4) and p=0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS.
CONCLUSIONS: We recommend prioritising testing for germline mutations in patients with HN-PGLs and T-PGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.

Lepoutre-Lussey C, Thibault C, Buffet A, et al.
From Nf1 to Sdhb knockout: Successes and failures in the quest for animal models of pheochromocytoma.
Mol Cell Endocrinol. 2016; 421:40-8 [PubMed] Related Publications
Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors characterized by a high frequency of hereditary forms. Based on transcriptome classification, PPGL can be classified in two different clusters. Cluster 1 tumors are caused by mutations in SDHx, VHL and FH genes and are characterized by a pseudohypoxic signature. Cluster 2 PPGL carry mutations in RET, NF1, MAX or TMEM127 genes and display an activation of the MAPK and mTOR signaling pathways. Many genetically engineered and allografted mouse models have been generated these past 30 years to investigate the mechanisms of PPGL tumorigenesis and test new therapeutic strategies. Among them, only Cluster 2-related models have been successful while no Cluster 1-related knockout mouse was so far reported to develop a PPGL. In this review, we present an overview of existing, successful or not, PPGL models, and a description of our own experience on the quest of Sdhb knockout mouse models of PPGL.

Zhu WD, Wang ZY, Chai YC, et al.
Germline mutations and genotype-phenotype associations in head and neck paraganglioma patients with negative family history in China.
Eur J Med Genet. 2015; 58(9):433-8 [PubMed] Related Publications
The aim of this study was to assess the frequency of germline mutations and to explore genotype-phenotype associations in Chinese head and neck paraganglioma (HNPGL) patients without family history. Twenty-six Chinese patients with a diagnosis of HNPGL(14 male and 12 female, respectively)were recruited, who were followed up from 2000 to 2012. Genomic DNA was obtained from resected tumor tissues and peripheral blood samples. Seven genes, Succinate dehydrogenase complex A,B,C,D (SDHA, SDHB, SDHC, SDHD), succinate dehydrogenase complex assembly factor 2 (SDHAF2), TMEM127 (transmembrane protein 127) and VHL (Von Hippel-Lindau), were screened by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) was performed to search for potential large deletions or duplications of SDHB, SDHC, SDHD, SDHAF1 and SDHAF2. The total frequency of germline mutations was 30.8% (8/26), including 5 cases with missense mutation p.Met1Ile in SDHD, 1 case with missense mutation p.Tyr216Cys in SDHB, and 1 case with a novel truncation mutation p.Gln44Ter in SDHAF2. MLPA showed one patient with malignant HNPGL had heterozygous deletions of exon1, 2, 3, 7 and 8 in SDHB. Mutations in SDHD were the leading cause of HNPGL in this study. Mutation carriers were younger than non-mutation carriers (p < 0.01) and more likely to suffer from multiple tumors (p = 0.048), especially with mutations in SDHD. The presence of mutation was associated with the development of larger tumors (p = 0.021). This study confirmed that the missense mutation p.Met1Ile at the start codon in SDHD was a hotspot in chinese patients with HNPGLs. We recommend genetic analysis in patients below 45 years, especially SDHD gene.

Bugalho MJ, Silva AL, Domingues R
Coexistence of paraganglioma/pheochromocytoma and papillary thyroid carcinoma: a four-case series analysis.
Fam Cancer. 2015; 14(4):603-7 [PubMed] Related Publications
The paraganglioma (PGL)/pheochromocytoma (PHEO)-papillary thyroid carcinoma (PTC) dyad has been reported rarely. Whether the association is coincidental or results from an underlying genetic predisposition is difficult to ascertain. We analyzed clinical and molecular data on four unrelated patients identified and treated by one of us (MJB) at a tertiary center. Patients were screened for germline variants in a panel of candidate genes: RET, VHL, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, PTEN, CDKN1B. All patients were female; median age at diagnosis of PGL/PHEO was 45 years and at diagnosis of PTC was 49.5 years. Only one patient had family history of thyroid cancer. PTC was multifocal in 2 cases, of the classical type in 2 cases and of the follicular type in 2 cases. Two patients harbored heterozygous germline variants of uncertain significance in the SDHB gene: Ser163Pro and Ala3Gly. The -79T>C polymorphism in the CDKN1B gene was present in all patients (3 in homozygous and 1 in heterozygous state). Results deriving from a comprehensive analysis of a panel of genes suggest that there is no single explanation for the association PGL/PHEO-PTC. It may occur through different mechanisms such as the combinatorial effect of different genetic variants, be a coincidental association or, alternatively, result from genetic variants in genes still awaiting identification.

Crona J, Backman S, Maharjan R, et al.
Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis.
Clin Cancer Res. 2015; 21(19):4451-60 [PubMed] Related Publications
PURPOSE: Pheochromocytoma and paraganglioma (PPGL) patients display heterogeneity in the clinical presentation and underlying genetic cause. The degree of inter- and intratumor genetic heterogeneity has not yet been defined.
EXPERIMENTAL DESIGN: In PPGLs from 94 patients, we analyzed LOH, copy-number variations, and mutation status of SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, NF1, RET, TMEM127, MAX, and HRAS using high-density SNP array and targeted deep sequencing, respectively. Genetic heterogeneity was determined through (i) bioinformatics analysis of individual samples that estimated absolute purity and ploidy from SNP array data and (ii) comparison of paired tumor samples that allowed reconstruction of phylogenetic trees.
RESULTS: Mutations were found in 61% of the tumors and correlated with specific patterns of somatic copy-number aberrations (SCNA) and degree of nontumoral cell admixture. Intratumor genetic heterogeneity was observed in 74 of 136 samples using absolute bioinformatics estimations and in 22 of 24 patients by comparison of paired samples. In addition, a low genetic concordance was observed between paired primary tumors and distant metastases. This allowed for reconstructing the life history of individual tumors, identifying somatic mutations as well as copy-number loss of 3p and 11p (VHL subgroup), 1p (Cluster 2), and 17q (NF1 subgroup) as early events in PPGL tumorigenesis.
CONCLUSIONS: Genomic landscapes of PPGL are specific to mutation subtype and characterized by genetic heterogeneity both within and between tumor lesions of the same patient.

Hernandez KG, Ezzat S, Morel CF, et al.
Familial pheochromocytoma and renal cell carcinoma syndrome: TMEM127 as a novel candidate gene for the association.
Virchows Arch. 2015; 466(6):727-32 [PubMed] Related Publications
Germline mutations in Von Hippel-Lindau (VHL), succinate dehydrogenase subunit B (SDHB), SDHC, and SDHD have been detected in individuals with synchronous or metachronous pheochromocytoma/paraganglioma (PHEO/PGL) and renal cell carcinoma (RCC). Most recently, FH and TMEM127 germline mutations, which are known to cause familial PHEO/PGL, have also been identified in familial RCC. We report the first case of an individual with both a PHEO and a multilocular clear cell RCC driven by a novel germline mutation in the TMEM127 gene. Morphologically, both the PHEOs and multilocular RCC were indistinguishable from those associated with VHL disease. However, at the biochemical level, the predominant adrenergic catecholamine profile distinguishes this presentation from SDH- and VHL-related PHEOs. This case justifies the prioritization of genetic testing for germline TMEM127 in individuals with RCC and PHEO with a predominantly adrenergic phenotype.

von Dobschuetz E, Leijon H, Schalin-Jäntti C, et al.
A registry-based study of thyroid paraganglioma: histological and genetic characteristics.
Endocr Relat Cancer. 2015; 22(2):191-204 [PubMed] Related Publications
The precise diagnosis of thyroid neoplasias will guide surgical management. Primary thyroid paraganglioma has been rarely reported. Data on prevalence, immunohistochemistry (IHC), and molecular genetics in a systematic series of such patients are pending. We performed a multinational population-based study on thyroid paraganglioma and analyzed prevalence, IHC, and molecular genetics. Patients with thyroid paraganglioma were recruited from the European-American-Head-and-Neck-Paraganglioma-Registry. Demographic and clinical data were registered. Histopathology and IHC were re-investigated. All patients with thyroid paraganglioma underwent molecular genetic analyses of the SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, TMEM127, and MAX genes. Analyses included Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) for detection of large rearrangements. Of 947 registrants, eight candidates were initially identified. After immunohistochemical analyses of these eight subjects, 5 (0.5%) were confirmed to have thyroid paraganglioma. IHC was positive for chromogranin, synaptophysin, and S-100 and negative for calcitonin in all five thyroid paragangliomas, whereas the three excluded candidate tumors stained positive for pan-cytokeratin, a marker excluding endocrine tumors. Germline variants, probably representing mutations, were found in four of the five confirmed thyroid paraganglioma cases, two each in SDHA and SDHB, whereas the excluded cases had no mutations in the tested genes. Thyroid paraganglioma is a finite entity, which must be differentiated from medullary thyroid carcinoma, because medical, surgical, and genetic management for each is different. Notably, approximately 80% of thyroid paragangliomas are associated with germline variants, with implications for additional tumors and a potential risk for the family. As opposed to sporadic tumors, surgical management and extent of resection are different for heritable tumors, each guided by the precise gene involved.

Dénes J, Swords F, Rattenberry E, et al.
Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.
J Clin Endocrinol Metab. 2015; 100(3):E531-41 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence.
OBJECTIVE: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL.
DESIGN: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples.
SETTING: The study was conducted at university hospitals.
PATIENTS: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study.
OUTCOME: Outcomes included genetic screening and clinical characteristics.
RESULTS: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context.
CONCLUSIONS: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Casey R, Garrahy A, Tuthill A, et al.
Universal genetic screening uncovers a novel presentation of an SDHAF2 mutation.
J Clin Endocrinol Metab. 2014; 99(7):E1392-6 [PubMed] Related Publications
CONTEXT: Hereditary pheochromocytoma/paraganglioma (PC/PGL) accounts for up to 60% of previously considered sporadic tumors. Guidelines suggest that phenotype should guide genetic testing. Next-generation sequencing technology can simultaneously sequence 9 of the 18 known susceptibility genes in a timely, cost-efficient manner.
OBJECTIVE: Our aim was to confirm that universal screening is superior to targeted testing in patients with histologically confirmed PC and PGL.
METHODS: In two tertiary referral hospitals in Ireland, NGS was carried out on all histologically confirmed cases of PC/PGL diagnosed between 2004 and 2013. The following susceptibility genes were sequenced: VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. A multiplex ligation-dependent probe amplification analysis was performed in VHL, SDHB, SDHC, SDHD, and SDHAF2 genes to detect deletions and duplications.
RESULTS: A total of 31 patients were tested, 31% (n = 10) of whom were found to have a genetic mutation. Of those patients with a positive genotype, phenotype predicted genotype in only 50% (n = 5). Significant genetic mutations that would have been missed in our cohort by phenotypic evaluation alone include a mutation in TMEM127, two mutations in SDHAF2, and two mutations in RET. Target testing would have identified three of the latter mutations based on age criteria. However, 20% of patients (n = 2) would not have satisfied any criteria for targeted testing including one patient with a novel presentation of an SDHAF2 mutation.
CONCLUSION: This study supports the value of universal genetic screening for all patients with PC/PGL.

Welander J, Andreasson A, Juhlin CC, et al.
Rare germline mutations identified by targeted next-generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma.
J Clin Endocrinol Metab. 2014; 99(7):E1352-60 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Pheochromocytomas and paragangliomas have a highly diverse genetic background, with a third of the cases carrying a germline mutation in 1 of 14 identified genes.
OBJECTIVE: This study aimed to evaluate next-generation sequencing for more efficient genetic testing of pheochromocytoma and paraganglioma and to establish germline and somatic mutation frequencies for all known susceptibility genes.
DESIGN: A targeted next-generation sequencing approach on an Illumina MiSeq instrument was used for a mutation analysis in 86 unselected pheochromocytoma and paraganglioma tumor samples. The study included the genes EGLN1, EPAS1, KIF1Bβ, MAX, MEN1, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL. RESULTS were verified in tumor and constitutional DNA with Sanger sequencing.
RESULTS: In all cases with clinical syndromes or known germline mutations, a mutation was detected in the expected gene. Among 68 nonfamilial tumors, 32 mutations were identified in 28 of the samples (41%), including germline mutations in EGLN1, KIF1Bβ, SDHA, SDHB, and TMEM127 and somatic mutations in EPAS1, KIF1Bβ, MAX, NF1, RET, and VHL, including one double monoallelic EPAS1 mutation.
CONCLUSIONS: Targeted next-generation sequencing proved to be fast and cost effective for the genetic analysis of pheochromocytoma and paraganglioma. More than half of the tumors harbored mutations in the investigated genes. Notably, 7% of the apparently sporadic cases carried germline mutations, highlighting the importance of comprehensive genetic testing. KIF1Bβ, which previously has not been investigated in a large cohort, appears to be an equally important tumor suppressor as MAX and TMEM127 and could be considered for genetic testing of these patients.

Crona J, Nordling M, Maharjan R, et al.
Integrative genetic characterization and phenotype correlations in pheochromocytoma and paraganglioma tumours.
PLoS One. 2014; 9(1):e86756 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: About 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS. Selective screening for germline mutations is routinely performed in clinical management of these diseases. Testing for somatic alterations is not performed on a regular basis because of limitations in interpreting the results.
AIM: The purpose of the study was to investigate genetic events and phenotype correlations in a large cohort of PCC and PGL tumours.
METHODS: A total of 101 tumours from 89 patients with PCC and PGL were re-sequenced for a panel of 10 disease causing genes using automated Sanger sequencing. Selected samples were analysed with Multiplex Ligation-dependent Probe Amplification and/or SNParray.
RESULTS: Pathogenic genetic variants were found in tumours from 33 individual patients (37%), 14 (16%) were discovered in constitutional DNA and 16 (18%) were confirmed as somatic. Loss of heterozygosity (LOH) was observed in 1/1 SDHB, 11/11 VHL and 3/3 NF1-associated tumours. In patients with somatic mutations there were no recurrences in contrast to carriers of germline mutations (P = 0.022). SDHx/VHL/EPAS1 associated cases had higher norepinephrine output (P = 0.03) and lower epinephrine output (P<0.001) compared to RET/NF1/H-RAS cases.
CONCLUSION: Somatic mutations are frequent events in PCC and PGL tumours. Tumour genotype may be further investigated as prognostic factors in these diseases. Growing evidence suggest that analysis of tumour DNA could have an impact on the management of these patients.

Blanchet EM, Gabriel S, Martucci V, et al.
18F-FDG PET/CT as a predictor of hereditary head and neck paragangliomas.
Eur J Clin Invest. 2014; 44(3):325-332 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hereditary head and neck paragangliomas (HNPGLs) account for at least 35% of all HNPGLs, most commonly due to germline mutations in SDHx susceptibility genes. Several studies about sympathetic paragangliomas have shown that (18)F-FDG PET/CT was not only able to detect and localize tumours, but also to characterize tumours ((18)F-FDG uptake being linked to SDHx mutations). However, the data concerning (18)F-FDG uptake specifically in HNPGLs have not been addressed. The aim of this study was to evaluate the relationship between (18)F-FDG uptake and the SDHx mutation status in HNPGL patients.
METHODS: (18)F-FDG PET/CT from sixty HNPGL patients were evaluated. For all lesions, we measured the maximum standardized uptake values (SUVmax), and the uptake ratio defined as HNPGL-SUVmax over pulmonary artery trunk SUVmean (SUVratio). Tumour sizes were assessed on radiological studies.
RESULTS: Sixty patients (53.3% with SDHx mutations) were evaluated for a total of 106 HNPGLs. HNPGLs-SUVmax and SUVratio were highly dispersed (1.2-30.5 and 1.0-17.0, respectively). The HNPGL (18)F-FDG uptake was significantly higher in SDHx versus sporadic tumours on both univariate and multivariate analysis (P = 0.002). We developed two models for calculating the probability of a germline SDHx mutation. The first one, based on a per-lesion analysis, had an accuracy of 75.5%. The second model, based on a per-patient analysis, had an accuracy of 80.0%.
CONCLUSIONS: (18)F-FDG uptake in HNPGL is strongly dependent on patient genotype. Thus, the degree of (18)F-FDG uptake in these tumours can be used clinically to help identify patients in whom SDHx mutations should be suspected.

Qin Y, Deng Y, Ricketts CJ, et al.
The tumor susceptibility gene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function.
Hum Mol Genet. 2014; 23(9):2428-39 [PubMed] Free Access to Full Article Related Publications
TMEM127 is an endosome-associated tumor suppressor gene in pheochromocytomas, neuroendocrine tumors that can co-occur with renal cell carcinomas (RCCs). TMEM127 loss leads to increased mTOR signaling. However, the spectrum of tumors with TMEM127 mutation and how TMEM127 and mTOR interact in tumorigenesis remains unknown. Here, we report that germline TMEM127 mutations occur in RCCs and that some mutant proteins, unlike wild-type (WT) TMEM127, fail to cooperate with activated early endosomal GTPase, Rab5, to inhibit mTOR signaling. Tmem127-null mouse embryonic fibroblasts (MEFs) are deficient in generating early-to-late hybrid endosomes upon constitutive Rab5 activation, a defect rescued by WT, but not mutant, TMEM127. This endosomal dysfunction results in diminished mTOR colocalization with Rab5-positive vesicles. Conversely, active, lysosomal-bound mTOR is increased in Tmem127-null MEFs, which also display enhanced lysosomal biogenesis. Our data map the tumor-suppressive properties of TMEM127 to modulation of mTOR function in the endolysosome, a feature that may contribute to both pheochromocytoma and RCC pathogenesis.

Bacca A, Chiacchio S, Zampa V, et al.
Role of 18F-DOPA PET/CT in diagnosis and follow-up of adrenal and extra-adrenal paragangliomas.
Clin Nucl Med. 2014; 39(1):14-20 [PubMed] Related Publications
PURPOSE: The objective of this study was to establish the clinical value of F-DOPA PET/CT in patients with adrenal and extra-adrenal paragangliomas (PGLs).
METHODS: Twenty-six consecutive patients with suspected or recurrent PGL underwent MR (and/or CT) and F-DOPA PET/CT. Histopathology confirmation was obtained in 20 cases. Genetic analysis on known susceptibility genes for PGL (VHL, RET, SDHx, TMEM127) was available in 13 patients.
RESULTS: Fourteen patients were affected by PGL (8 with head/neck location, 6 with abdominal/thoracic location), whereas 12 showed masses of other origin. Three patients proved to be SDHD, 1 SDHB, 2 SDHC, and 1 TMEM127 mutation carriers. F-DOPA PET/CT showed pathological uptake in 13 of 26 patients. The procedure identified all PGLs except one with bone metastases (previous malignant adrenal PGL). No uptake was found in patients without proven PGL. Thus, in the whole group, F-DOPA PET/CT sensitivity was 92.8%, and specificity was 100% with positive and negative predictive values of 100% and 92.3%, respectively. Total diagnostic accuracy was 96.2%. In the head/neck subgroup, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were 100%. In the abdominal location, sensitivity was 80% and specificity was 100%, and positive and negative predictive values were 100% and 91.7%, respectively. Abdominal diagnostic accuracy was 93.7%. Radiotracer uptake was superimposable in head/neck PGLs versus abdominal PGLs and in mutated versus wild-type patients.
CONCLUSIONS: The high diagnostic performance of F-DOPA PET/CT showed this technique to be a useful tool in detecting PGLs, above all those located at the head/neck site, regardless of the genetic pattern.

Hussain I, Husain Q, Baredes S, et al.
Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management.
J Neurosurg. 2014; 120(2):321-30 [PubMed] Related Publications
Paragangliomas are rare, slow-growing tumors that frequently arise in the head and neck, with the carotid bodies and temporal bone of the skull base being the most common sites. These neoplasms are histologically similar to pheochromocytomas that form in the adrenal medulla and are divided into sympathetic and parasympathetic subtypes based on functionality. Skull base and head and neck region paragangliomas (SHN-PGs) are almost always derived from parasympathetic tissue and rarely secrete catecholamines. However, they can cause significant morbidity by mass effect on various cranial nerves and major blood vessels. While surgery for SHN-PG can be curative, postoperative deficits and recurrences make these lesions challenging to manage. Multiple familial syndromes predisposing individuals to development of paragangliomas have been identified, all involving mutations in the succinate dehydrogenase complex of mitochondria. Mutations in this enzyme lead to a state of "pseudohypoxia" that upregulates various angiogenic, survival, and proliferation factors. Moreover, familial paraganglioma syndromes are among the rare inherited diseases in which genomic imprinting occurs. Recent advances in gene arrays and transcriptome/exome sequencing have identified an alternate mutation in sporadic SHN-PG, which regulates proto-oncogenic pathways independent of pseudohypoxia-induced factors. Collectively these findings demonstrate that paragangliomas of the skull base and head and neck region have a distinct genetic signature from sympathetic-based paragangliomas occurring below the neck, such as pheochromocytomas. Paragangliomas serve as a unique model of primarily surgically treated neoplasms whose future will be altered by the elucidation of their genomic complexities. In this review, the authors present an analysis of the molecular genetics of SHN-PG and provide future directions in patient care and the development of novel therapies.

Bausch B, Wellner U, Bausch D, et al.
Long-term prognosis of patients with pediatric pheochromocytoma.
Endocr Relat Cancer. 2014; 21(1):17-25 [PubMed] Related Publications
A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.

Andreasson A, Kiss NB, Caramuta S, et al.
The VHL gene is epigenetically inactivated in pheochromocytomas and abdominal paragangliomas.
Epigenetics. 2013; 8(12):1347-54 [PubMed] Free Access to Full Article Related Publications
Pheochromocytoma (PCC) and abdominal paraganglioma (PGL) are neuroendocrine tumors that present with clinical symptoms related to increased catecholamine levels. About a third of the cases are associated with constitutional mutations in pre-disposing genes, of which some may also be somatically mutated in sporadic cases. However, little is known about inactivating epigenetic events through promoter methylation in these very genes. Using bisulphite pyrosequencing we assessed the methylation density of 11 PCC/PGL disease genes in 96 tumors (83 PCCs and 13 PGLs) and 34 normal adrenal references. Gene expression levels were determined by quantitative RT-PCR. Both tumors and normal adrenal samples exhibited low methylation index (MetI) in the EGLN1 (PDH2), MAX, MEN1, NF1, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127 promoters, not exceeding 10% in any of the samples investigated. Aberrant RET promoter methylation was observed in two cases only. For the VHL gene we found increased MetI in tumors as compared with normal adrenals (57% vs. 27%; P<0.001), in malignant vs. benign tumors (63% vs. 55%; P<0.05), and in PGL vs. PCC (66% vs. 55%; P<0.0005). Decreased expression of the VHL gene was observed in all tumors compared with normal adrenals (P<0.001). VHL MetI and gene expressions were inversely correlated (R = -0.359, P<0.0001). Our results show that the VHL gene promoter has increased methylation compared with normal adrenals (MetI>50%) in approximately 75% of PCCs and PGLs investigated, highlighting the role of VHL in the development of these tumors.

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