RESUMO
Gastrointestinal stromal tumors (GIST) are rare digestive tumors. Activating KIT mutations are the most common molecular alteration in these patients, identified in approximately 70 % of cases, followed by PDGFRA mutations (10-15 %), of which the D842V mutation accounts for most cases. Succinate dehydrogenase (SDH) deficiency and alterations involving NF1, BRAFV600E, RAS or NTRK genes are rare molecular subgroups. In advanced GIST, treatment is based on tyrosine kinase inhibitors, including imatinib, which has been the standard first-line treatment since the early 2000s, with sunitinib and regorafenib as second- and third-line standards, respectively. Two new compounds have recently been evaluated in patients with advanced GIST. Ripretinib has become the validated fourth-line therapy for patients with KIT or PDGFRA non-D842V mutations, and avapritinib has been shown to be effective in patients with D842V mutations who were previously resistant to validated treatments. Avapritinib is now the recommended first-line treatment in this subgroup and may represent an additional option, whose place remains to be clarified, in pre-treated patients without D842V mutations. Specific treatments are available or under evaluation for some rare subgroups, and new therapeutic strategies are likely to further improve the management of advanced GIST in the coming years. This overview summarizes the results of recent trials and the place of these new molecules, as well as the main strategies under development for advanced GIST.
Assuntos
Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Antineoplásicos/uso terapêutico , Complexo II de Transporte de Elétrons/deficiência , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/uso terapêutico , Erros Inatos do Metabolismo , Doenças Mitocondriais , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Succinato Desidrogenase/genética , Sunitinibe/uso terapêuticoRESUMO
Apart from the oncometabolite succinate, little studies have appeared on extra-mitochondrial pathways in Succinate Dehydrogenase (SDH) genetic deficiency. The role of NADH/NAD+ redox status and dependent pathways was recently emphasized. Therein, fatty acid (FA) metabolism data were collected here in 30 patients with a loss of function (LOF) variant in one SDHx gene (either with a pheochromocytoma/paraganglioma (PPGL) or asymptomatic) and in 22 wild-type SDHx controls (with PPGL or asymptomatic). Blood acylcarnitines in two patients, peroxisomal biomarkers, very long-chain saturated FA (VLCFA), and C20 to C24 n-3 polyunsaturated fatty acids (PUFA), in all patients were measured by mass spectrometry. Preliminary data showed elevated even and odd long- and very long-chain acylcarnitines in two patients with a SDHB variant. In the whole series, no abnormalities were observed in biomarkers of peroxisomal ß-oxidation (C27-bile acids, VLCFAs and phytanic/pristanic acids) in SDHx patients. However, an increased hexaene to pentaene PUFA ratio ([TetraHexaenoic Acid + DocosaHexaenoic Acid]/[n-3 DocosaPentaenoic Acid + EicosaPentaenoic Acid]) was noticed in patients with SDHC/SDHD variants vs patients with SDHA/SDHB variants or controls, suggesting a higher degree of unsaturation of PUFAs. Within the group with a SDHx variant, Eicosapentaenoate/Tetracosahexaenoate ratio, as an empiric index of shortening/elongation balance, discriminated patients with PPGL from asymptomatic ones. Present findings argue for stimulated elongation of saturated FAs, changes in shortening/elongation balance and desaturation rates of C20-C24 PUFAs in SDH-deficient patients with PPGL. Overall, oxidation of NADH sustained by these pathways might reflect or impact glycolytic NAD+ recycling and hence tumor proliferation.
Assuntos
Neoplasias das Glândulas Suprarrenais , Ácidos Graxos/sangue , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/genética , Ácidos e Sais Biliares , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Complexo II de Transporte de Elétrons/deficiência , Humanos , Erros Inatos do Metabolismo , Doenças Mitocondriais , Mutação , NAD/metabolismo , Paraganglioma/genética , Paraganglioma/metabolismo , Paraganglioma/patologia , Feocromocitoma/genética , Succinato Desidrogenase/genética , Ácido Succínico/metabolismoRESUMO
Effective T cell-mediated immune responses require the proper allocation of metabolic resources to sustain growth, proliferation, and cytokine production. Epigenetic control of the genome also governs T cell transcriptome and T cell lineage commitment and maintenance. Cellular metabolic programs interact with epigenetic regulation by providing substrates for covalent modifications of chromatin. By using complementary genetic, epigenetic, and metabolic approaches, we revealed that tricarboxylic acid (TCA) cycle flux fueled biosynthetic processes while controlling the ratio of succinate/α-ketoglutarate (α-KG) to modulate the activities of dioxygenases that are critical for driving T cell inflammation. In contrast to cancer cells, where succinate dehydrogenase (SDH)/complex II inactivation drives cell transformation and growth, SDH/complex II deficiency in T cells caused proliferation and survival defects when the TCA cycle was truncated, blocking carbon flux to support nucleoside biosynthesis. Replenishing the intracellular nucleoside pool partially relieved the dependence of T cells on SDH/complex II for proliferation and survival. SDH deficiency induced a proinflammatory gene signature in T cells and promoted T helper 1 and T helper 17 lineage differentiation. An increasing succinate/α-KG ratio in SDH-deficient T cells promoted inflammation by changing the pattern of the transcriptional and chromatin accessibility signatures and consequentially increasing the expression of the transcription factor, PR domain zinc finger protein 1. Collectively, our studies revealed a role of SDH/complex II in allocating carbon resources for anabolic processes and epigenetic regulation in T cell proliferation and inflammation.
Assuntos
Epigênese Genética , Succinato Desidrogenase , Proliferação de Células , Cromatina , Complexo II de Transporte de Elétrons/deficiência , Humanos , Inflamação/genética , Ácidos Cetoglutáricos/química , Ácidos Cetoglutáricos/metabolismo , Ácidos Cetoglutáricos/farmacologia , Erros Inatos do Metabolismo , Doenças Mitocondriais , Nucleosídeos , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , SuccinatosRESUMO
A fascinating class of familial paraganglioma (PGL) neuroendocrine tumors is driven by the loss of the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) resulting in succinate accumulation as an oncometabolite and other metabolic derangements. Here, we exploit a Saccharomyces cerevisiae yeast model of SDH loss where accumulating succinate, and possibly reactive oxygen species, poison a dioxygenase enzyme required for sulfur scavenging. Using this model, we performed a chemical suppression screen for compounds that relieve dioxygenase inhibition. After testing 1280 pharmaceutically active compounds, we identified meclofenoxate HCl and its hydrolysis product, dimethylaminoethanol (DMAE), as suppressors of dioxygenase intoxication in SDH-loss yeast cells. We show that DMAE acts to alter metabolism so as to normalize the succinate:2-ketoglutarate ratio, improving dioxygenase function. This study raises the possibility that oncometabolite effects might be therapeutically suppressed by drugs that rewire metabolism to reduce the flux of carbon into pathological metabolic pathways.
Assuntos
Dioxigenases , Paraganglioma , Dioxigenases/metabolismo , Complexo II de Transporte de Elétrons/deficiência , Humanos , Erros Inatos do Metabolismo , Doenças Mitocondriais , Paraganglioma/patologia , Saccharomyces cerevisiae/metabolismo , Succinato Desidrogenase/metabolismo , SuccinatosRESUMO
Isolated deficiency of complex II is a rare inborn error of metabolism, accounting for approximately 2% of mitochondrial diseases. Mitochondrial complex II deficiency is predominantly seen in cases with bi-allelic SDHA mutations. To our knowledge, only 11 patients and five pathogenic variants have been reported for the SDHB gene. Our patient had a severe clinical presentation with seizures and sepsis, and died at the age of 2 months. Muscle biopsy analysis was compatible with mitochondrial myopathy with complex II deficiency. The family was given a molecular diagnosis for their child 2 years after his death via a clinical exome test of a frozen muscle biopsy specimen and a novel homozygous missense variant c.592 A>G (p.Ser198Gly) in SDHB gene was detected by next-generation sequencing. Here, we present another patient with a novel homozygous SDHB variant causing severe complex II deficiency and early death.
Assuntos
Complexo II de Transporte de Elétrons/deficiência , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/genética , Succinato Desidrogenase/genética , Consanguinidade , Complexo II de Transporte de Elétrons/genética , Evolução Fatal , Humanos , Recém-Nascido , MasculinoRESUMO
BACKGROUND: Complex II is an essential component of the electron transport chain, linking it with the tricarboxylic acid cycle. Its four subunits are encoded in the nuclear genome, and deleterious variants in these genes, including SDHA (OMIM 600857), are associated with a wide range of symptoms including neurological disease, cardiomyopathy, and neoplasia (paraganglioma-pheochromocytomas (PGL/PCC), and gastrointestinal stromal tumors). Deleterious variants of SDHA are most frequently associated with Leigh and Leigh-like syndromes. METHODS AND RESULTS: Here, we describe a case of a 9-year-old boy with tremor, nystagmus, hypotonia, developmental delay, significant ataxia, and progressive cerebellar atrophy. He was found to have biallelic variants in SDHA, a known pathogenic variant (c.91C>T (p.R31*)), and a variant of unknown significance (c.454G>A (p.E152K)). Deficient activity of complexes II and III was detected in fibroblasts from the patient consistent with a diagnosis of a respiratory chain disorder. CONCLUSION: We, therefore, consider whether c.454G>A (p.E152K) is, indeed, a pathogenic variant, and what implications it has for family members who carry the same variant.
Assuntos
Ataxia Cerebelar/genética , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Complexo II de Transporte de Elétrons/deficiência , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/genética , Células Cultivadas , Ataxia Cerebelar/patologia , Criança , Complexo II de Transporte de Elétrons/genética , Complexo II de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/genética , Fibroblastos/metabolismo , Humanos , Masculino , Erros Inatos do Metabolismo/patologia , Doenças Mitocondriais/patologia , MutaçãoRESUMO
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/genéticaRESUMO
Mitochondrial complex II (succinate:ubiquinone oxidoreductase) is the smallest complex of the oxidative phosphorylation system, a tetramer of just 140 kDa. Despite its diminutive size, it is a key complex in two coupled metabolic pathways - it oxidises succinate to fumarate in the tricarboxylic acid cycle and the electrons are used to reduce FAD to FADH2, ultimately reducing ubiquinone to ubiquinol in the respiratory chain. The biogenesis and assembly of complex II is facilitated by four ancillary proteins, all of which are autosomally-encoded. Numerous pathogenic defects have been reported which describe two broad clinical manifestations, either susceptibility to cancer in the case of single, heterozygous germline variants, or a mitochondrial disease presentation, almost exclusively due to bi-allelic recessive variants and associated with an isolated complex II deficiency. Here we present a compendium of pathogenic gene variants that have been documented in the literature in patients with an isolated mitochondrial complex II deficiency. To date, 61 patients are described, harbouring 32 different pathogenic variants in four distinct complex II genes: three structural subunit genes (SDHA, SDHB and SDHD) and one assembly factor gene (SDHAF1). Many pathogenic variants result in a null allele due to nonsense, frameshift or splicing defects however, the missense variants that do occur tend to induce substitutions at highly conserved residues in regions of the proteins that are critical for binding to other subunits or substrates. There is phenotypic heterogeneity associated with defects in each complex II gene, similar to other mitochondrial diseases.
Assuntos
Complexo II de Transporte de Elétrons/deficiência , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/genética , Succinato Desidrogenase/genética , Adolescente , Adulto , Criança , Pré-Escolar , Complexo II de Transporte de Elétrons/genética , Complexo II de Transporte de Elétrons/metabolismo , Feminino , Fumaratos/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Redes e Vias Metabólicas/genética , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/metabolismo , Pessoa de Meia-Idade , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/metabolismo , Fosforilação Oxidativa , Proteínas/genética , Ácido Succínico/metabolismoRESUMO
Succinate dehydrogenase (SDH) is uniquely tasked with a dual role in the essential energy-producing processes of a cell. Although SDH subunits and assembly factors form part of the same enzyme complex, mutations in their respective genes lead to significantly different clinical phenotypes. Remarkable discoveries in the last 17 years have led to the delineation of the SDH complex deficiency syndrome and its multiple pathogenic branches. Here we provide an updated overview of SDH deficiency in order to raise awareness of its multiple connotations including nonneoplastic associations and pertinent features of the continually growing list of SDH-mutant tumors so as to better direct genetic counseling and predict prognosis.
Assuntos
Complexo II de Transporte de Elétrons/genética , Complexos Multienzimáticos , Neoplasias/genética , Succinato Desidrogenase/genética , Complexo II de Transporte de Elétrons/deficiência , Humanos , Mutação , Neoplasias/enzimologia , Neoplasias/patologia , Fenótipo , Succinato Desidrogenase/deficiênciaRESUMO
AIMS: We sought to determine if some unclassified renal cell carcinomas (RCCs) in children and young adults that are characterised by predominantly eosinophilic cytoplasm are related to the recently described succinate dehydrogenase (SDH)-deficient RCC, fumarate hydratase (FH)-deficient RCC or eosinophilic solid and cystic (ESC) RCC. METHODS AND RESULTS: We reviewed 33 unclassified RCCs with predominantly eosinophilic cytoplasm in patients aged 35 years or younger. Immunohistochemistry (IHC) for SDHB, FH and CK20 (a marker of ESC) was performed in all cases. IHC for 2-succinocysteine (2SC) was performed on RCC with loss of FH labelling. Four RCC (12%) (median age 18 years) demonstrated loss of FH labelling as well as aberrant 2SC labelling, and were thus classified as FH-deficient RCCs. Importantly, none of these cases demonstrated the characteristic macronucleoli typical of FH-deficient RCC. Eight RCC (24%) (median age 20.5 years) demonstrated loss of SDHB and were reclassified as SDH-deficient RCCs. Importantly, only four of eight SDH-deficient RCC demonstrated the characteristic cytoplasmic vacuoles and inclusions of typical SDH-deficient RCC. Ten RCC (30%) (median age 27 years) were reclassified as ESC RCCs. Four of 10 ESC RCC were multifocal (one bilateral), four of 10 ESC RCC occurred in males and one patient presented with liver and lung metastases, all not described previously in ESC. Eleven RCC (33%) remained unclassified. CONCLUSIONS: Pathologists should have a low threshold for performing FH, SDHB and CK20 IHC when confronted with unclassified eosinophilic RCC or 'oncocytoma' in young patients.
Assuntos
Carcinoma de Células Renais/patologia , Eosinófilos/patologia , Neoplasias Renais/patologia , Adolescente , Adulto , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/genética , Complexo II de Transporte de Elétrons/deficiência , Feminino , Fumarato Hidratase/deficiência , Humanos , Neoplasias Renais/classificação , Neoplasias Renais/genética , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/epidemiologia , Doenças Mitocondriais/complicações , Doenças Mitocondriais/epidemiologia , Hipotonia Muscular/complicações , Hipotonia Muscular/epidemiologia , Síndromes Neoplásicas Hereditárias/epidemiologia , Transtornos Psicomotores/complicações , Transtornos Psicomotores/epidemiologia , Adulto JovemRESUMO
Biallelic likely pathogenic variants in SLC52A2 and SLC52A3 cause riboflavin transporter deficiency. It is characterized by muscle weakness, ataxia, progressive ponto-bulbar palsy, amyotrophy, and sensorineural hearing loss. Oral riboflavin halts disease progression and may reverse symptoms. We report two new patients whose clinical and biochemical features were mimicking mitochondrial myopathy. Patient 1 is an 8-year-old male with global developmental delay, axial and appendicular hypotonia, ataxia, and sensorineural hearing loss. His muscle biopsy showed complex II deficiency and ragged red fibers consistent with mitochondrial myopathy. Whole exome sequencing revealed a homozygous likely pathogenic variant in SLC52A2 (c.917G>A; p.Gly306Glu). Patient 2 is a 14-month-old boy with global developmental delay, respiratory insufficiency requiring ventilator support within the first year of life. His muscle biopsy revealed combined complex II + III deficiency and ragged red fibers consistent with mitochondrial myopathy. Whole exome sequencing identified a homozygous likely pathogenic variant in SCL52A3 (c.1223G>A; p.Gly408Asp). We report two new patients with riboflavin transporter deficiency, caused by mutations in two different riboflavin transporter genes. Both patients presented with complex II deficiency. This treatable neurometabolic disorder can mimic mitochondrial myopathy. In patients with complex II deficiency, riboflavin transporter deficiency should be included in the differential diagnosis to allow early treatment and improve neurodevelopmental outcome.
Assuntos
Complexo III da Cadeia de Transporte de Elétrons/deficiência , Complexo II de Transporte de Elétrons/deficiência , Proteínas de Membrana Transportadoras/genética , Miopatias Mitocondriais/genética , Receptores Acoplados a Proteínas G/genética , Biópsia , Criança , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Progressão da Doença , Complexo II de Transporte de Elétrons/genética , Complexo III da Cadeia de Transporte de Elétrons/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Lactente , Masculino , Erros Inatos do Metabolismo , Doenças Mitocondriais , Miopatias Mitocondriais/fisiopatologia , Riboflavina/genética , Riboflavina/metabolismo , Deficiência de Riboflavina/genética , Deficiência de Riboflavina/fisiopatologiaRESUMO
Succinate dehydrogenase (SDH) is a heterotetrameric nuclear encoded mitochondrial protein complex which plays a role in the citric acid cycle and the electron transfer chain. Germline mutations in SDHA are associated with Leigh syndrome. Mutations in SDHB, SDHC and SDHD are found in an increasing number of neoplasms, most notably paragangliomas and wild-type gastrointestinal stromal tumours. SDH deficiency in these tumours has important prognostic implications, and also provides a novel target for molecular therapy. In this article, we outline the structure and function of SDH and provide a summary of its role in various diseases.
Assuntos
Predisposição Genética para Doença , Succinato Desidrogenase/genética , Cardiomiopatia Dilatada/genética , Complexo II de Transporte de Elétrons/deficiência , Complexo II de Transporte de Elétrons/genética , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Marcadores Genéticos , Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/genética , Humanos , Doença de Leigh/genética , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Neoplasias do Sistema Nervoso/genética , Paraganglioma/genética , Succinato Desidrogenase/deficiênciaRESUMO
Mitochondrial respiratory chain dysfunction causes a variety of life-threatening diseases affecting about 1 in 4300 adults. These diseases are genetically heterogeneous, but have the same outcome; reduced activity of mitochondrial respiratory chain complexes causing decreased ATP production and potentially toxic accumulation of metabolites. Severity and tissue specificity of these effects varies between patients by unknown mechanisms and treatment options are limited. So far most research has focused on the complexes themselves, and the impact on overall cellular metabolism is largely unclear. To illustrate how computer modelling can be used to better understand the potential impact of these disorders and inspire new research directions and treatments, we simulated them using a computer model of human cardiomyocyte mitochondrial metabolism containing over 300 characterised reactions and transport steps with experimental parameters taken from the literature. Overall, simulations were consistent with patient symptoms, supporting their biological and medical significance. These simulations predicted: complex I deficiencies could be compensated using multiple pathways; complex II deficiencies had less metabolic flexibility due to impacting both the TCA cycle and the respiratory chain; and complex III and IV deficiencies caused greatest decreases in ATP production with metabolic consequences that parallel hypoxia. Our study demonstrates how results from computer models can be compared to a clinical phenotype and used as a tool for hypothesis generation for subsequent experimental testing. These simulations can enhance understanding of dysfunctional mitochondrial metabolism and suggest new avenues for research into treatment of mitochondrial disease and other areas of mitochondrial dysfunction.
Assuntos
Trifosfato de Adenosina/metabolismo , Deficiência de Citocromo-c Oxidase , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Complexo II de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/deficiência , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Simulação por Computador , HumanosRESUMO
Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is an emerging provisional entity included in the 2013 International Society of Urological Pathology Vancouver Classification. Most genomic alterations in patients with SDH-deficient RCCs involve the SDHB subunit, and the associated renal tumors have loss of immunohistochemical SDHB expression and distinctive morphologic features. Renal tumors less commonly possess genomic alterations involving the SDHC and SDHD subunits, but no SDHA alterations have as yet been described. Here we identified a novel SDHA homozygous deletion in an aggressive variant of RCC diagnosed initially as unclassified type in a 54-year-old patient. A search for novel actionable mutations by comprehensive genomic profiling based on clinical next-generation sequencing evaluating entire coding regions of 315 cancer-related genes, including all SDH subunits, was performed. Sequencing identified a novel 17 kbp homozygous deletion of 9 SDHA exons on chromosome 5p15. SDHA and SDHB immunohistochemistry further confirmed that the homozygous deletion led to the loss of SDHA and SDHB protein expression. Histologically, the tumor had a mixed pattern of high-grade papillary and collecting duct carcinoma and distinctive pale eosinophilic cytoplasmic inclusions similar to those described in SDHB-deficient RCC. This is the first report that identifies SDHA inactivation in RCC. Additional studies utilizing comprehensive genomic profiling, immunohistochemistry, and careful morphologic evaluation are needed both prospectively and retrospectively to identify the group of RCCs harboring SDHA genomic alterations.
Assuntos
Carcinoma de Células Renais/genética , Complexo II de Transporte de Elétrons/deficiência , Complexo II de Transporte de Elétrons/genética , Neoplasias Renais/genética , Carcinoma de Células Renais/patologia , Perfilação da Expressão Gênica , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Deleção de Sequência , Succinato Desidrogenase/deficiência , Succinato Desidrogenase/genéticaRESUMO
Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex participating in the Krebs cycle and electron transfer of oxidative phosphorylation. These tumors, discovered during the past 15 years, often occur in young patients and include 15% of paragangliomas, 7% of gastric gastrointestinal stromal tumors (GISTs), and <1% of renal cell carcinomas and pituitary adenomas. SDH-deficient tumors have lost SDH complex activity via bi-allelic genomic losses or epigenetic silencing. This deficiency is oncogenic, activating pseudohypoxia signaling. SDH deficiency has to be suspected in the above-cited tumor types presenting at a young age. Immunohistochemical testing of tumor tissue for SDHB loss is diagnostic.
Assuntos
Complexo II de Transporte de Elétrons/deficiência , Complexo II de Transporte de Elétrons/genética , Neoplasias/enzimologia , Neoplasias/genética , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/genética , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/genética , Humanos , Imuno-Histoquímica , Neoplasias Renais/enzimologia , Neoplasias Renais/genética , Paraganglioma/enzimologia , Paraganglioma/genética , Neoplasias Hipofisárias/enzimologia , Neoplasias Hipofisárias/genéticaRESUMO
Mitochondrial disorders resulting from an isolated deficiency of complex II of the respiratory chain is rarely reported. The phenotypic spectrum associated with these disorders is heterogeneous and still expanding. This report describes a patient who presented with myopathy, dilated cardiomyopathy, and pontine signal changes on magnetic resonance imaging. Muscle biopsy showed total absence of succinate dehydrogenase on enzyme histochemistry, negative succinate dehydrogenase subunit A (SDHA) activity on immunohistochemistry, and ultrastructural evidence of mitochondrial aggregates of varying sizes confirming the diagnosis of complex II deficiency. A unique phenotype with complex II deficiency is reported.
Assuntos
Encefalopatias Metabólicas/etiologia , Cardiomiopatias/etiologia , Complexo II de Transporte de Elétrons/deficiência , Miopatias Mitocondriais/patologia , Ponte/patologia , Encefalopatias Metabólicas/patologia , Feminino , Humanos , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/fisiopatologia , Adulto JovemRESUMO
Loss of function of the succinate dehydrogenase complex characterizes a rare group of human tumors including some gastrointestinal stromal tumors, paragangliomas, renal carcinomas, and pituitary adenomas, and these can all be characterized as SDH-deficient tumors. Approximately 7.5% of gastric gastrointestinal stromal tumors are SDH-deficient and not driven by KIT/PDGFRA mutations, as are most other GISTs. The occurrence of SDH-deficient GISTs is restricted to stomach, and they typically occur in children and young adults representing a spectrum of clinical behavior from indolent to progressive. Slow progression is a common feature even after metastatic spread has taken place, and many patients live years with metastases. SDH-deficient GISTs have characteristic morphologic features including multinodular gastric wall involvement, often multiple separate tumors, common lymphovascular invasion, and occasional lymph node metastases. Diagnostic is the loss of succinate dehydrogenase subunit B (SDHB) from the tumor cells and this can be practically assessed by immunohistochemistry. SDHA is lost in cases associated with SDHA mutations. Approximately half of the patients have SDH subunit gene mutations, often germline and most commonly A (30%), and B, C or D (together 20%), with both alleles inactivated in the tumor cells according to the classic tumor suppressor gene model. Half of the cases are not associated with SDH-mutations and epigenetic silencing of the SDH complex is the possible pathogenesis. Extensive genomic methylation has been observed in these tumors, which is in contrast with other GISTs. SDH-loss causes succinate accumulation and activation of pseudohypoxia signaling via overexpression of HIF-proteins. Activation of insulin-like growth factor 1-signaling is also typical of these tumors. SDH-deficient GISTs are a unique group of GISTs with an energy metabolism defect as the key oncogenic mechanism. This article is part of a Directed Issue entitled: Rare Cancers.
Assuntos
Complexo II de Transporte de Elétrons/genética , Tumores do Estroma Gastrointestinal/genética , Proteínas de Membrana/genética , Succinato Desidrogenase/genética , Metilação de DNA/genética , Complexo II de Transporte de Elétrons/deficiência , Metabolismo Energético/genética , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/epidemiologia , Tumores do Estroma Gastrointestinal/patologia , Predisposição Genética para Doença , Humanos , Proteínas de Membrana/deficiência , Mutação , Somatomedinas/metabolismo , Succinato Desidrogenase/deficiênciaRESUMO
BACKGROUND: Defects of the mitochondrial respiratory chain complex II (succinate dehydrogenase (SDH) complex) are extremely rare. Of the four nuclear encoded proteins composing complex II, only mutations in the 70 kDa flavoprotein (SDHA) and the recently identified complex II assembly factor (SDHAF1) have been found to be causative for mitochondrial respiratory chain diseases. Mutations in the other three subunits (SDHB, SDHC, SDHD) and the second assembly factor (SDHAF2) have so far only been associated with hereditary paragangliomas and phaeochromocytomas. Recessive germline mutations in SDHB have recently been associated with complex II deficiency and leukodystrophy in one patient. METHODS AND RESULTS: We present the clinical and molecular investigations of the first patient with biochemical evidence of a severe isolated complex II deficiency due to compound heterozygous SDHD gene mutations. The patient presented with early progressive encephalomyopathy due to compound heterozygous p.E69 K and p.*164Lext*3 SDHD mutations. Native polyacrylamide gel electrophoresis and western blotting demonstrated an impaired complex II assembly. Complementation of a patient cell line additionally supported the pathogenicity of the novel identified mutations in SDHD. CONCLUSIONS: This report describes the first case of isolated complex II deficiency due to recessive SDHD germline mutations. We therefore recommend screening for all SDH genes in isolated complex II deficiencies. It further emphasises the importance of appropriate genetic counselling to the family with regard to SDHD mutations and their role in tumorigenesis.
Assuntos
Complexo II de Transporte de Elétrons/deficiência , Genes Recessivos/genética , Erros Inatos do Metabolismo , Doenças Mitocondriais , Encefalomiopatias Mitocondriais , Mutação/genética , Succinato Desidrogenase/genética , Sequência de Aminoácidos , Criança , Evolução Fatal , Feminino , Humanos , Dados de Sequência Molecular , Alinhamento de SequênciaRESUMO
Gastrointestinal stromal tumors (GISTs) usually harbor activating mutations in KIT or PDGFRA, which promote tumorigenesis through activation of growth factor receptor signaling pathways. Around 15% of GISTs in adults and >90% in children lack such mutations ('wild-type' GISTs). Most gastric wild-type GISTs show loss of function of the Krebs cycle enzyme complex succinate dehydrogenase (SDH). However, the mechanism by which SDH deficiency drives tumorigenesis is unclear. Loss of SDH leads to succinate accumulation, which is thought to inhibit α-ketoglutarate-dependent dioxygenase enzymes, such as the TET family of DNA hydroxylases. TET proteins catalyze the conversion of 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), which is required for subsequent DNA demethylation. Thus, TET-mediated 5-hmC production alters global DNA methylation patterns and may thereby influence gene expression. We investigated 5-hmC levels in a cohort of genotyped GISTs to determine whether loss of SDH was associated with inhibition of TET activity. 5-hmC levels were examined via immunohistochemistry in a cohort of 30 genotyped GISTs, including 10 SDH-deficient tumors (5 SDHA mutant; 1 SDHB mutant; 1 SDHC mutant; 3 unknown), 14 tumors with KIT mutations (10 in exon 11; 3 in exon 9; 1 in exon 17), and 6 tumors with PDGFRA mutations (all in exon 18). Staining for 5-hmC was negative in 9 of 10 (90%) SDH-deficient GISTs, 3 of 14 (21%) KIT-mutant GISTs, and 1 of 6 (17%) PDGFRA-mutant GISTs. The other SDH-deficient GIST showed weak staining for 5-hmC. Thus, 5-hmC was absent in nearly all SDH-deficient GISTs. These findings suggest that SDH deficiency may promote tumorigenesis through accumulation of succinate and inhibition of dioxygenase enzymes. Inhibition of TET activity may, in turn, alter global DNA methylation and gene expression in SDH-deficient tumors.
Assuntos
Biomarcadores Tumorais/análise , Citosina/análogos & derivados , Tumores do Estroma Gastrointestinal/enzimologia , Succinato Desidrogenase/deficiência , 5-Metilcitosina/análogos & derivados , Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Citosina/análise , Análise Mutacional de DNA , Regulação para Baixo , Complexo II de Transporte de Elétrons/deficiência , Éxons , Tumores do Estroma Gastrointestinal/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Proteínas de Membrana/deficiência , Mutação , Fenótipo , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Succinato Desidrogenase/genéticaRESUMO
BACKGROUND: Isolated complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses. The succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD) are autosomally-encoded and transcribe the conjugated heterotetramers of complex II via the action of two known assembly factors (SDHAF1 and SDHAF2). Only a handful of reports describe inherited SDH gene defects as a cause of paediatric mitochondrial disease, involving either SDHA (Leigh syndrome, cardiomyopathy) or SDHAF1 (infantile leukoencephalopathy). However, all four SDH genes, together with SDHAF2, have known tumour suppressor functions, with numerous germline and somatic mutations reported in association with hereditary cancer syndromes, including paraganglioma and pheochromocytoma. METHODS AND RESULTS: Here, we report the clinical and molecular investigations of two patients with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to novel SDH gene mutations; the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations, while the second patient presented with hypotonia and leukodystrophy with elevated brain succinate demonstrated by MR spectroscopy due to a novel, homozygous p.Asp48Val SDHB mutation. Western blotting and BN-PAGE studies confirmed decreased steady-state levels of the relevant SDH subunits and impairment of complex II assembly. Evidence from yeast complementation studies provided additional support for pathogenicity of the SDHB mutation. CONCLUSIONS: Our report represents the first example of SDHB mutation as a cause of inherited mitochondrial respiratory chain disease and extends the SDHA mutation spectrum in patients with isolated complex II deficiency.