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1.
Genes Genet Syst ; 96(2): 55-69, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34039789

RESUMO

The pathogenesis of pheochromocytoma and paraganglioma (PCPG) catecholamine-producing tumors is exceedingly complicated. Here, we sought to identify important genes affecting the prognosis and survival rate of patients suffering from PCPG. We analyzed 95 samples obtained from two microarray data series, GSE19422 and GSE60459, from the Gene Expression Omnibus (GEO) repository. First, differentially expressed genes (DEGs) were identified by comparing 87 PCPG tumor samples and eight normal adrenal tissue samples using R language. The GEO2R tool and Venn diagram software were applied to the Database for Annotation, Visualization and Integrated Discovery (DAVID) to analyze Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO). We further employed Cytoscape with the Molecular Complex Detection (MCODE) tool to make protein-protein interactions visible for the Search Tool for Retrieval of Interacting Genes (STRING). These procedures resulted in 30 candidate DEGs, which were subjected to Kaplan-Meier analysis and validated by Gene Expression Profiling Interactive Analysis (GEPIA) to determine their influence on overall survival rate. Finally, we identified ALDH3A2 and AKR1B1, two genes in the glycerolipid metabolism pathway, as being particularly enriched in PCPG tumors and correlated with T and B tumor-infiltrating immune cells. Our results suggest that these two DEGs are closely associated with the prognosis of malignant PCPG tumors.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Biomarcadores Tumorais/genética , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/metabolismo , Biomarcadores Tumorais/metabolismo , Redes Reguladoras de Genes , Humanos , Paraganglioma/metabolismo , Paraganglioma/patologia , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Mapas de Interação de Proteínas , Análise de Sobrevida , Transcriptoma
2.
Eur J Endocrinol ; 185(1): 179-191, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33983135

RESUMO

Objective: Within the past decade, important genetic drivers of pheochromocytoma and paraganglioma (PPGLs) development have been identified. The pathophysiological mechanism that translates these alterations into functional autonomy and potentially malignant behavior has not been elucidated in detail. Here we used MALDI-mass spectrometry imaging (MALDI-MSI) of formalin-fixed paraffin-embedded tissue specimens to comprehensively characterize the metabolic profiles of PPGLs. Design and methods: MALDI-MSI was conducted in 344 PPGLs and results correlated with genetic and phenotypic information. We experimentally silenced genetic drivers by siRNA in PC12 cells to confirm their metabolic impact in vitro. Results: Tissue abundance of kynurenine pathway metabolites such as xanthurenic acid was significantly lower (P = 2.35E-09) in the pseudohypoxia pathway cluster 1 compared to PPGLs of the kinase-driven PPGLs cluster 2. Lower abundance of xanthurenic acid was associated with shorter metastasis-free survival (log-rank tests P = 7.96E-06) and identified as a risk factor for metastasis independent of the genetic status (hazard ratio, 32.6, P = 0.002). Knockdown of Sdhb and Vhl in an in vitro model demonstrated that inositol metabolism and sialic acids were similarly modulated as in tumors of the respective cluster. Conclusions: The present study has identified distinct tissue metabolomic profiles of PPGLs in relation to tumor genotypes. In addition, we revealed significantly altered metabolites in the kynurenine pathway in metastatic PPGLs, which can aid in the prediction of its malignant potential. However, further validation studies will be required to confirm our findings.


Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Espectrometria de Massas/métodos , Metaboloma , Paraganglioma/patologia , Feocromocitoma/patologia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Adulto , Animais , Estudos de Coortes , Progressão da Doença , Feminino , Estudos de Associação Genética , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Metástase Neoplásica , Células PC12 , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/metabolismo , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/metabolismo , Prognóstico , Ratos , Análise Serial de Tecidos/métodos
3.
Am J Surg Pathol ; 45(9): 1264-1273, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33826547

RESUMO

Alpha-inhibin expression has been reported in pheochromocytomas and paragangliomas (PPGLs). We analyzed alpha-inhibin immunohistochemistry in 77 PPGLs (37 pheochromocytomas [PCCs] and 40 paragangliomas) and correlated the results with catecholamine profile, tumor size, Ki-67 labeling index, succinate dehydrogenase B subunit and carbonic anhydrase IX (CAIX) staining, and genetic pathogenesis. PPGLs were classified as pseudohypoxic cluster 1 disease with documented VHL mutation or SDHx mutation or biochemical phenotype, whereas NF1-driven and RET-driven PPGLs and those with a mature secretory (adrenergic or mixed adrenergic and noradrenergic) phenotype were classified as cluster 2 disease. The Cancer Genome Atlas data on INHA expression in PPGLs was examined. Alpha-inhibin was positive in 43 PPGLs (56%). Ki-67 labeling indices were 8.07% and 4.43% in inhibin-positive and inhibin-negative PPGLs, respectively (P<0.05). Alpha-inhibin expression did not correlate with tumor size. Alpha-inhibin was expressed in 92% of SDHx-related and 86% of VHL-related PPGLs. CAIX membranous staining was found in 8 of 51 (16%) tumors, including 1 SDHx-related PCC and all 5 VHL-related PCCs. NF1-driven and RET-driven PPGLs were negative for alpha-inhibin and CAIX. Alpha-inhibin was expressed in 77% of PPGLs with a pseudohypoxia signature, and 20% of PPGLs without a pseudohypoxia signature (P<0.05). PPGLs with a mature secretory phenotype were negative for CAIX. The Cancer Genome Atlas data confirmed higher expression of INHA in cluster 1 than in cluster 2 PPGLs. This study identifies alpha-inhibin as a highly sensitive (90.3%) marker for SDHx/VHL-driven pseudohypoxic PPGLs. Although CAIX has low sensitivity, it is the most specific biomarker of VHL-related pathogenesis. While alpha-inhibin cannot replace succinate dehydrogenase B subunit immunohistochemistry for detection of SDHx-related disease, it adds value in prediction of cluster 1 disease. Importantly, these data emphasize that alpha-inhibin is not a specific marker of adrenal cortical differentiation, as it is also expressed in PCCs.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Inibinas/metabolismo , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Biomarcadores Tumorais/metabolismo , Anidrase Carbônica IX/metabolismo , Humanos , Paraganglioma/metabolismo , Paraganglioma/patologia , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Sensibilidade e Especificidade
4.
Int J Biochem Cell Biol ; 134: 105949, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33609747

RESUMO

Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours. So far, over 20 causative genes have been identified, of which the most frequent and strongest indicator for malignancies are mutations in succinate dehydrogenase subunit B. No curative therapy is available for patients with metastases resulting in poor prognosis. Therapy development has been hindered by lack of suitable model systems. The succinate dehydrogenase complex is located in the inner membrane of the mitochondria and plays a crucial role in the oxidative phosphorylation chain and the tricarboxylic acid-cycle. Succinate dehydrogenase deficiency results in accumulation of the oncometabolite succinate inducing hypoxia inducible factor stabilization, deoxyribonucleic acid and histone methylation inhibition, and impaired production of adenosine triphosphate. It remains unknown which combination of pathways and/or triggers are decisive for metastases development. In this review, the role of mitochondria in malignant succinate dehydrogenase subunit B-associated phaeochromocytomas and paragangliomas and implications for mitochondria as therapeutic target are discussed.


Assuntos
Neoplasias das Glândulas Suprarrenais/enzimologia , Complexo II de Transporte de Elétrons/deficiência , Erros Inatos do Metabolismo/enzimologia , Mitocôndrias/enzimologia , Doenças Mitocondriais/enzimologia , Paraganglioma/enzimologia , Feocromocitoma/enzimologia , Succinato Desidrogenase/metabolismo , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Animais , Complexo II de Transporte de Elétrons/genética , Complexo II de Transporte de Elétrons/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Mutação , Paraganglioma/genética , Paraganglioma/metabolismo , Paraganglioma/patologia , Feocromocitoma/genética , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Succinato Desidrogenase/genética
5.
World Neurosurg ; 143: e391-e399, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32745642

RESUMO

OBJECTIVE: Surgical resection is the therapy of choice in head and neck paraganglioma but is associated with considerable morbidity. For treatment of inoperable or progressive disease, less aggressive adjuvant options are warranted. This study assessed effectiveness and safety of peptide receptor radionuclide therapy (PRRT) with lutetium-177-DOTATATE for head and neck paraganglioma with emphasis on response assessment. METHODS: A retrospective analysis of 7 patients with head and neck paraganglioma treated with PPRT between May 2014 and October 2016 was performed. Three patients had jugulotympanic paraganglioma, 3 patients had carotid body tumors, and 1 patient had a combination of both. Patients underwent PRRT after discussion in the local tumor board regarding progressive disease, inoperability, or lack of other adjuvant options. All patients underwent 3-5 cycles of PRRT. Treatment response was evaluated by gallium-68-DOTATATE positron emission tomography/computed tomography and contrast-enhanced computed tomography or magnetic resonance imaging. Outcome measures were two-dimensional tumor diameters and total tumor volumes. RESULTS: Median patient age was 60 years (interquartile range: 14-84 years). All patients had stable disease at posttherapy assessment. Decreasing tumor volumes were found in 4 patients. Clinical symptoms improved in 2 patients. No progression or adverse events occurred during a median follow-up of 39 months (interquartile range: 35-47 months). CONCLUSIONS: Somatostatin receptor-targeted therapy using lutetium-177-DOTATATE shows promising effectiveness with a high safety profile. Patients in whom surgical morbidity outweighs oncologic benefit should be informed about PRRT as a treatment option.


Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/radioterapia , Octreotida/análogos & derivados , Compostos Organometálicos/metabolismo , Paraganglioma/metabolismo , Paraganglioma/radioterapia , Receptores de Somatostatina/metabolismo , Adolescente , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/administração & dosagem , Octreotida/metabolismo , Compostos Organometálicos/administração & dosagem , Paraganglioma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/metabolismo , Estudos Retrospectivos
6.
Ann Otol Rhinol Laryngol ; 129(11): 1135-1143, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32486832

RESUMO

BACKGROUND: Recommendations regarding head and neck paragangliomas (HNPGL) have undergone a fundamental reorientation in the last decade as a result of increased understanding of the genetic and pathophysiologic basis of these disorders. OBJECTIVE: We aim to provide an overview of HNPGL and recent discoveries regarding their molecular genetics, along with updated recommendations on workup, treatment, and surveillance, and their implications for otolaryngologists treating patients with these disorders. RESULTS: SDHx susceptibility gene mutations, encoding subunits of the enzyme succinate dehydrogenase (SDH), give rise to the Hereditary Pheochromocytoma/Paraganglioma Syndromes. SDHA, SDHB, SDHC, SDHD, and SDHAF2 mutations each result in unique phenotypes with distinct penetrance and risk for variable tumor development as well as metastasis. Genetic and biochemical testing is recommended for every patient with HNPGL. Multifocal disease should be managed in multi-disciplinary fashion. Patients with SDHx mutations require frequent biochemical screening and whole-body imaging, as well as lifelong follow-up with an expert in hereditary pheochromocytoma and paraganglioma syndromes. CONCLUSION: Otolaryngologists are likely to encounter patients with HNPGL. Keeping abreast of the latest recommendations, especially regarding genetic testing, workup for additional tumors, multi-disciplinary approach to care, and need for lifelong surveillance, will help otolaryngologists appropriately care for these patients.


Assuntos
Neoplasias de Cabeça e Pescoço/genética , Proteínas de Membrana/genética , Mutação , Otorrinolaringologistas , Paraganglioma/genética , Testes Genéticos , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Paraganglioma/metabolismo , Fenótipo
7.
Metabolism ; 110: 154297, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32562798

RESUMO

BACKGROUND: Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting. METHODS: Metabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts. RESULTS: Components of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts. CONCLUSIONS: This study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.


Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Poliaminas Biogênicas/antagonistas & inibidores , Paraganglioma/tratamento farmacológico , Feocromocitoma/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Animais , Poliaminas Biogênicas/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino , Metabolômica , Camundongos , Mutação , Paraganglioma/genética , Paraganglioma/metabolismo , Feocromocitoma/genética , Feocromocitoma/metabolismo , Succinato Desidrogenase/genética , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Clin Endocrinol Metab ; 105(9)2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32575117

RESUMO

CONTEXT: TMEM127 is a poorly known tumor suppressor gene associated with pheochromocytomas, paragangliomas, and renal carcinomas. Our incomplete understanding of TMEM127 function has limited our ability to predict variant pathogenicity. PURPOSE: To better understand the function of the transmembrane protein TMEM127 we undertook cellular and molecular evaluation of patient-derived germline variants. DESIGN: Subcellular localization and steady-state levels of tumor-associated, transiently expressed TMEM127 variants were compared to the wild-type protein using immunofluorescence and immunoblot analysis, respectively, in cells genetically modified to lack endogenous TMEM127. Membrane topology and endocytic mechanisms were also assessed. RESULTS: We identified 3 subgroups of mutations and determined that 71% of the variants studied are pathogenic or likely pathogenic through loss of membrane-binding ability, stability, and/or internalization capability. Investigation into an N-terminal cluster of missense variants uncovered a previously unrecognized transmembrane domain, indicating that TMEM127 is a 4- transmembrane, not a 3-transmembrane domain-containing protein. Additionally, a C-terminal variant with predominant plasma membrane localization revealed an atypical, extended acidic, dileucine-based motif required for TMEM127 internalization through clathrin-mediated endocytosis. CONCLUSION: We characterized the functional deficits of several germline TMEM127 variants and identified novel structure-function features of TMEM127. These findings will assist in determining pathogenicity of TMEM127 variants and will help guide future studies investigating the cellular role of TMEM127.


Assuntos
Membrana Celular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Substituição de Aminoácidos , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Células HEK293 , Humanos , Proteínas de Membrana/química , Mutagênese Sítio-Dirigida , Mutação/fisiologia , Paraganglioma/genética , Paraganglioma/metabolismo , Feocromocitoma/genética , Feocromocitoma/metabolismo , Transporte Proteico/genética , Distribuição Tecidual
12.
Biomed Res Int ; 2020: 4150735, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190664

RESUMO

Objective: The aim of this study was to investigate the expression of Snail, galectin-3, and IGF1R in benign and malignant pheochromocytoma and paraganglioma (PPGL) and explore their role in the diagnosis of malignant PPGL. Methods: We retrospectively collected and analyzed surgical tumor tissue from 226 patients initially diagnosed with PPGL who underwent surgery from Jan. 2009 to Jan. 2016 at West China Hospital, Sichuan University. We observed and quantified the expression of Snail, galectin-3, and IGF1R in paraffin-embedded samples by immunohistochemical staining. Results: The significant difference in survival time among the three groups (benign PHEO, benign PGL, and potentially malignant PPGL) was compared by Kaplan-Meier survival analysis. The positive staining of Snail, galectin-3, and IGF1R in the benign PHEO group was significantly lower than that in the other three groups (P < 0.001). The Kaplan-Meier survival plots indicated that the survival time of the patients with intense positive staining was significantly lower than that of the patients with weak positive staining. Conclusion: The intense expression of Snail, galectin-3, and IGF1R may be valuable indicators for the diagnosis of malignant PPGL.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Biomarcadores Tumorais/metabolismo , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Receptor IGF Tipo 1/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/cirurgia , Adulto , Idoso , China , Diagnóstico Diferencial , Feminino , Galectina 3/metabolismo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Paraganglioma/metabolismo , Paraganglioma/cirurgia , Feocromocitoma/metabolismo , Feocromocitoma/cirurgia , Estudos Retrospectivos , Software
14.
Theranostics ; 10(8): 3518-3532, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32206105

RESUMO

Rationale: Deregulation of metabolism and induction of vascularization are major hallmarks of cancer. Using a new multimodal preclinical imaging instrument, we explored a sequence of events leading to sunitinib-induced resistance in a murine model of paraganglioma (PGL) invalidated for the expression of succinate dehydrogenase subunit B (Sdhb -/-). Methods: Two groups of Sdhb -/- tumors bearing mice were treated with sunitinib (6 weeks) or vehicle (3 weeks). Concurrent Positron Emission Tomography (PET) with 2' -deoxy-2'-[18F]fluoro-D-glucose (FDG), Computed Tomography (CT) and Ultrafast Ultrasound Imaging (UUI) imaging sessions were performed once a week and ex vivo samples were analyzed by western blots and histology. Results: PET-CT-UUI enabled to detect a rapid growth of Sdhb-/- tumors with increased glycolysis and vascular development. Sunitinib treatment prevented tumor growth, vessel development and reduced FDG uptake at week 1 and 2 (W1-2). Thereafter, imaging revealed tumor escape from sunitinib treatment: FDG uptake in tumors increased at W3, followed by tumor growth and vessel development at W4-5. Perfused vessels were preferentially distributed in the hypermetabolic regions of the tumors and the perfused volume increased during escape from sunitinib treatment. Finally, initial changes in total lesion glycolysis and maximum vessel length at W1 were predictive of resistance to sunitinib. Conclusion: These results demonstrate an adaptive resistance of Sdhb -/- tumors to six weeks of sunitinib treatment. Early metabolic changes and delayed vessel architecture changes were detectable and predictable in vivo early during anti-angiogenic treatment. Simultaneous metabolic, anatomical and functional imaging can monitor precisely the effects of anti-angiogenic treatment of tumors.


Assuntos
Antineoplásicos/uso terapêutico , Neovascularização Patológica/diagnóstico por imagem , Paraganglioma/diagnóstico por imagem , Sunitinibe/uso terapêutico , Animais , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Feminino , Glucose-6-Fosfato/análogos & derivados , Glicólise , Camundongos , Camundongos Nus , Neovascularização Patológica/metabolismo , Neovascularização Patológica/prevenção & controle , Paraganglioma/tratamento farmacológico , Paraganglioma/metabolismo , Paraganglioma/patologia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Evasão Tumoral/efeitos dos fármacos , Ultrassonografia
15.
Ann Endocrinol (Paris) ; 81(1): 3-10, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32067697

RESUMO

BACKGROUND: Carbohydrate disorders are the most frequent metabolic disorders, affecting a significant proportion of patients with pheochromocytoma. OBJECTIVE: A retrospective study assessed the prevalence and progression of carbohydrate disorders in 204 patients (92 men, 112 women) with histologically proven pheochromocytoma diagnosed in a single specialized tertiary center during a 40-year period (1978-2017). One hundred were followed-up after tumor removal. RESULTS: Carbohydrate disorders were diagnosed in 49.5% of cases: 30.4% with diabetes and, 19.1% prediabetes. Subjects with carbohydrate disorders had significantly greater age at diagnosis and higher 24-hour urine metanephrine and normetanephrine concentrations than those with normal glucose tolerance. One-third of patients with diabetes achieved good glycemic control under oral treatment (54% on metformin monotherapy). One-third of patients overall required preoperative insulin treatment. Postoperative follow-up (100 patients; 5-year mean duration) showed reduced prevalence of diabetes (13% vs. 33%; P=0.0007) and prediabetes (12% vs. 24%; P=0.027). Almost 60% of subjects initially diagnosed with carbohydrate disorders recovered normal glucose tolerance after surgery; these subjects had significantly higher preoperative urine metanephrine/normetanephrine levels than those with persistent diabetes/prediabetes. Correlation analysis revealed a moderate negative relationship between urine metanephrine/normetanephrine concentration and the outcome of the carbohydrate disorders (Spearmen's Rho=-0.507; P=0.013). There was no significant difference according to pre- or postoperative prevalence of obesity (15% vs. 16%; P=0.845) or dyslipidemia (46% vs. 39%; P=0.316). CONCLUSIONS: Carbohydrate disorders affect approximately 50% of pheochromocytoma patients; 30% develop overt diabetes, which may be the only clinical manifestation in some rare cases. Pheochromocytoma-related diabetes is more likely to affect patients with predominant adrenaline secretion. It is often easy to control and usually requires oral antidiabetic treatment. Reversibility of carbohydrate disorders depend on severity, preoperative metanephrine level, age and weight.


Assuntos
Neoplasias das Glândulas Suprarrenais/epidemiologia , Transtornos do Metabolismo de Glucose/epidemiologia , Transtornos do Metabolismo de Glucose/patologia , Paraganglioma/epidemiologia , Feocromocitoma/epidemiologia , Adolescente , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/metabolismo , Adulto , Idoso , Glicemia/metabolismo , Criança , Progressão da Doença , Feminino , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/etiologia , Intolerância à Glucose/patologia , Transtornos do Metabolismo de Glucose/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Paraganglioma/complicações , Paraganglioma/metabolismo , Feocromocitoma/complicações , Feocromocitoma/metabolismo , Prevalência , Estudos Retrospectivos , Adulto Jovem
16.
Clin Nucl Med ; 45(3): e156-e157, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31714281

RESUMO

We report a case of an adult male patient with multifocal urinary bladder paragangliomas, which were negative on Ga-DOTATATE PET/CT scan, but positive on I-MIBG SPECT/CT scan. While the Ga-DOTA analog PET/CT exhibits superior performance in diagnosis and staging of pheochromocytoma and paraganglioma, our case demonstrates negative somatostatin receptor expression in this rare entity and indicates that I-MIBG SPECT/CT still plays a vital role in characterization of bladder paraganglioma.


Assuntos
3-Iodobenzilguanidina/metabolismo , Compostos Organometálicos/metabolismo , Paraganglioma/diagnóstico , Paraganglioma/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/metabolismo , Transporte Biológico , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Somatostatina/metabolismo
17.
Int J Cancer ; 146(8): 2326-2335, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31469413

RESUMO

Many long intergenic noncoding RNAs (lincRNAs) serve as cancer biomarkers for diagnosis or prognostication. To understand the role of lincRNAs in the rare neuroendocrine tumors pheochromocytoma and paraganglioma (PCPG), we performed first time in-depth characterization of lincRNA expression profiles and correlated findings to clinical outcomes of the disease. RNA-Seq data from patients with PCPGs and 17 other tumor types from The Cancer Genome Atlas and other published sources were obtained. Differential expression analysis and a machine-learning model were used to identify transcripts specific to PCPGs, as well as established PCPG molecular subtypes. Similarly, lincRNAs specific to aggressive PCPGs were identified, and univariate and multivariate analysis was performed for metastasis-free survival. The results were validated in independent samples using RT-PCR. From a pan-cancer context, PCPGs had a specific and unique lincRNA profile. Among PCPGs, five different molecular subtypes were identified corresponding to the established molecular classification. Upregulation of 13 lincRNAs was found to be associated with aggressive/metastatic PCPGs. RT-PCR validation confirmed the overexpression of four lincRNAs in metastatic compared to non-metastatic PCPGs. Kaplan-Meier analysis identified five lincRNAs as prognostic markers for metastasis-free survival of patients in three subtypes of PCPGs. Stratification of PCPG patients with a risk-score formulated using multivariate analysis of lincRNA expression profiles, presence of key driver mutations, tumor location, and hormone secretion profiles showed significant differences in metastasis-free survival. PCPGs thus exhibit a specific lincRNA expression profile that also corresponds to the established molecular subgroups and can be potential marker for the aggressive/metastatic PCPGs.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Tumores Neuroendócrinos/genética , Paraganglioma/genética , Feocromocitoma/genética , RNA não Traduzido/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Humanos , Metástase Neoplásica , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Paraganglioma/metabolismo , Paraganglioma/patologia , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Prognóstico , Intervalo Livre de Progressão , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA não Traduzido/biossíntese , Transcriptoma
18.
Clin Genet ; 97(1): 39-53, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30977114

RESUMO

Succinate dehydrogenase (SDH) mutations lead to the accumulation of succinate, which acts as an oncometabolite. Germline SDHx mutations predispose to paraganglioma (PGL) and pheochromocytoma (PCC), as well as to renal cell carcinoma and gastro-intestinal stromal tumors. The SDHx genes were the first tumor suppressor genes discovered which encode for a mitochondrial enzyme, thereby supporting Otto Warburg's hypothesis in 1926 that a direct link existed between mitochondrial dysfunction and cancer. Accumulation of succinate is the hallmark of tumorigenesis in PGL and PCC. Succinate accumulation inhibits several α-ketoglutarate dioxygenases, thereby inducing the pseudohypoxia pathway and causing epigenetic changes. Moreover, SDH loss as a consequence of SDHx mutations can lead to reprogramming of cell metabolism. Metabolomics can be used as a diagnostic tool, as succinate and other metabolites can be measured in tumor tissue, plasma and urine with different techniques. Furthermore, these pathophysiological characteristics provide insight into therapeutic targets for metastatic disease. This review provides an overview of the pathophysiology and clinical implications of oncometabolite succinate in SDHx mutations.


Assuntos
Neoplasias das Glândulas Suprarrenais/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Paraganglioma/metabolismo , Feocromocitoma/metabolismo , Succinato Desidrogenase/genética , Ácido Succínico/metabolismo , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Metabolômica , Mitocôndrias/enzimologia , Mitocôndrias/genética , Paraganglioma/genética , Paraganglioma/patologia , Paraganglioma/terapia , Feocromocitoma/genética , Feocromocitoma/patologia , Feocromocitoma/terapia , Transdução de Sinais/genética , Succinato Desidrogenase/metabolismo
19.
Ann Thorac Surg ; 109(2): e87-e90, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31279790

RESUMO

Management of functional intrathoracic sympathetic paragangliomas in succinate dehydrogenase subunit D (SDHD) mutation carriers is challenging, and there is no uniform guideline for treatment to date. The risks of potential malignant behavior and long-term cardiovascular morbidity have to be weighed against the risks of treatment complications. We report the multidisciplinary and shared decision-making approach that resulted in successful surgical removal of 3 paragangliomas in a SDHD mutation carrier.


Assuntos
DNA de Neoplasias/genética , Neoplasias de Cabeça e Pescoço/genética , Mutação , Neoplasias Primárias Múltiplas/genética , Succinato Desidrogenase/genética , Neoplasias Torácicas/genética , Adulto , Análise Mutacional de DNA , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/metabolismo , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/metabolismo , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Succinato Desidrogenase/metabolismo , Neoplasias Torácicas/diagnóstico , Neoplasias Torácicas/metabolismo
20.
Eur J Cell Biol ; 99(1): 151057, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810635

RESUMO

Succinate dehydrogenase (SDH), also named as complex II or succinate:quinone oxidoreductases (SQR) is a critical enzyme in bioenergetics and metabolism. This is because the enzyme is located at the intersection of oxidative phosphorylation and tricarboxylic acid cycle (TCA); the two major pathways involved in generating energy within cells. SDH is composed of 4 subunits and is assembled through a multi-step process with the aid of assembly factors. Not surprisingly malfunction of this enzyme has marked repercussions in metabolism leading to devastating tumors such as paraganglioma and pheochromocytoma. It is already known that mutations in the genes encoding subunits lead to tumorigenesis, but recent discoveries have indicated that mutations in the genes encoding the assembly factors also contribute to tumorigenesis. The mechanisms of pathogenesis of tumorigenesis have not been fully understood. However, a multitude of signaling pathways including succinate signaling was determined. We, here discuss how defective SDH may lead to tumor development at the molecular level and describe how yeast, as a model system, has contributed to understanding the molecular pathogenesis of tumorigenesis resulting from defective SDH.


Assuntos
Neoplasias das Glândulas Suprarrenais/enzimologia , Carcinogênese/metabolismo , Paraganglioma/enzimologia , Feocromocitoma/enzimologia , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/patogenicidade , Succinato Desidrogenase/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Animais , Humanos , Paraganglioma/metabolismo , Feocromocitoma/metabolismo , Saccharomyces cerevisiae/metabolismo , Succinato Desidrogenase/genética
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