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Phaeochromocytomas and paragangliomas (collectively termed PPGLs) are rare yet highly heritable neuroendocrine tumours, with over one third of cases associated with germline pathogenic variants (PVs) in numerous genes. PVs in succinate dehydrogenase subunit-A gene (SDHA) were initially implicated in hereditary PPGL in 2010 and SDHA has since become an important susceptibility gene accounting for up to 2.8 % of cases. However, it remains poorly understood, particularly regarding the clinical nature of SDHA PPGL, rates of recurrence and metastasis, and nature of metastatic disease. We present a narrative review of SDHA-related PPGL, covering pathophysiology, relevance to current clinical practice, and considerations for clinical genetics. We analyse a pool of 107 previously reported cases of SDHA-associated PPGL to highlight the spectrum of SDHA-related PPGL. Our analysis demonstrates SDHA PPGL occurs across a wide age-range (11-81 y) and affects men and women equally. SDHA PPGL typically present as single tumours (91%), usually occurring in the head and neck (46%) or abdomen (43%, including 15% with phaeochromocytomas). Metastatic disease was reported in 25.5% cases with bone (82%) and lymph nodes (71%) being the most common sites of metastasis, often identified many years after initial diagnosis. Family history of SDHA-related neoplasia was rare, reported in only 4% of cases. Understanding the clinical nature and risks associated with SDHA PVs is essential for facilitating optimal management of patients and their families.
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CONTEXT: Carriers of germline pathogenic variants (PVs) in succinate dehydrogenase type B (SDHB) are at increased risk of developing pheochromocytomas and paragangliomas (PPGLs). Understanding their outcomes can guide recommendations for risk assessment and early detection. OBJECTIVE: We performed a systematic review and meta-analysis of the following outcomes in SDHB PV carriers: age-specific risk of developing tumors, metastatic progression, second primary tumor development, and mortality. METHODS: PubMed, MEDLINE, and EMBASE were searched. Sixteen studies met the inclusion criteria and were sorted into 4 outcome categories: age-specific penetrance, metastatic disease, risk of second tumor, and mortality. We assessed heterogeneity and performed a meta-analysis across studies using a random-effects model with the DerSimonian and Laird method. RESULTS: Penetrance of PPGLs for nonproband/nonindex SDHB PV carriers by age 20 was 4% (95% CI, 3%-6%), 11% (95% CI, 8%-15%) by age 40, 24% (95% CI, 19%-31%) by age 60%, and 35% (95% CI, 25%-47%) by age 80. The overall risk of metastatic disease for nonproband/nonindex carriers with PPGLs was 9% (95%, CI 5%-16%) per lifetime. In all affected cases (combining both proband/index and nonproband/nonindex carriers with tumors), the risk of a second tumor was 24% (95% CI, 18%-31%) and all-cause 5-year mortality was 18% (95% CI, 6%-40%). CONCLUSION: Penetrance for PPGLs in SDHB PV carriers increases linearly with age. Affected carriers are at risk of developing and dying of metastatic disease, or of developing second tumors. Lifelong surveillance is appropriate.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Penetrância , Feocromocitoma , Succinato Desidrogenase , Humanos , Succinato Desidrogenase/genética , Paraganglioma/genética , Paraganglioma/patologia , Paraganglioma/mortalidade , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/mortalidade , Feocromocitoma/genética , Feocromocitoma/patologia , Feocromocitoma/mortalidade , Mutação em Linhagem Germinativa , Heterozigoto , Predisposição Genética para DoençaRESUMO
Phaeochromocytoma (PC) and paraganglioma (PGL) syndromes associated with germline pathogenic variants are associated with high morbidity and mortality. Establishing genotype-phenotype correlations within a young population is challenging due to their rare occurrence. OBJECTIVE: To describe genotype-phenotype correlations in paediatric and adolescent patients diagnosed with PC/PGL. To establish the incidence of PC/PGL in a young population and prevalence of germline pathogenic variants within this group. STUDY DESIGN: We conducted a cross-sectional study of patients diagnosed with a PC/PGL aged 0-21 years old who were reviewed within Familial Cancer Services within New South Wales and the Australian Capital Territory, Australia. RESULTS: A germline pathogenic variant was detected in 80% (24/30) of patients; SDHB: n=12, VHL: n=11, and MAX: n=1. Only patients harbouring a germline pathogenic variant reported a family history of syndromic tumours, those with apparently sporadic disease did not (62.5% versus 0%, p=0.02). All patients with VHL presented with an adrenal tumour compared with 25% of those with SDHB (100% versus 25%, p=0.01). Occurrence of multiple primary PC/PGL was seen in patients with VHL however was absent in patients with SDHB (36% versus 0%, p=0.03). Incidence rate of paediatric PC/PGL was 0.45 cases per million person years. CONCLUSIONS: PC/PGL diagnosed in children and adolescents were strongly associated with germline pathogenic variants in VHL or SDHB. These patients should be referred to specialist services for family counselling and genetic testing along followed by investigations for the detection of bilateral, multifocal or metastatic disease, and lifelong surveillance for recurrent disease.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Humanos , Adolescente , Criança , Recém-Nascido , Lactente , Pré-Escolar , Adulto Jovem , Adulto , Feocromocitoma/epidemiologia , Feocromocitoma/genética , Feocromocitoma/patologia , Estudos Transversais , Succinato Desidrogenase/genética , Austrália , Paraganglioma/epidemiologia , Paraganglioma/genética , Paraganglioma/diagnóstico , Estudos de Associação Genética , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/diagnósticoRESUMO
Phaeochromocytoma and paraganglioma are highly heritable tumours; half of those associated with a germline mutation are caused by mutations in genes for Krebs's cycle enzymes, including succinate dehydrogenase (SDH). Inheritance of SDH alleles is assumed to be Mendelian (probability of 50% from each parent). The departure from transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD). We sought to assess whether TRD occurs in the transmission of SDHB pathogenic variants (PVs). This study was conducted with 41 families of a discovery cohort from Royal North Shore Hospital, Australia, and 41 families from a validation cohort from St. Bartholomew's Hospital, United Kingdom (UK). Inclusion criteria were a clinically diagnosed SDHB PV and a pedigree available for at least two generations. TRD was assessed in 575 participants with the exact binomial test. The transmission ratio for SDHB PV was 0.59 (P = 0.005) in the discovery cohort, 0.67 (P < 0.001) in the validation cohort, and 0.63 (P < 0.001) in the combined cohort. No parent-of-origin effect was observed. TRD remained significant after adjusting for potential confounders: 0.67 (P < 0.001) excluding families with incomplete family size data; 0.58 (P < 0.001) when probands were excluded. TRD was also evident for SDHD PVs in a cohort of 81 patients from 13 families from the UK. The reason for TRD of SDHB and SDHD PVs is unknown, but we hypothesize a survival advantage selected during early embryogenesis. The existence of TRD for SDHB and SDHD has implications for reproductive counselling, and further research into the heterozygote state.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Succinato Desidrogenase , Humanos , Neoplasias das Glândulas Suprarrenais/genética , Alelos , Mutação em Linhagem Germinativa , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Padrões de HerançaRESUMO
Up to 40% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are hereditary. Germline mutations/deletions in fumarate hydratase ( FH ) cause hereditary leiomyomatosis and renal cell carcinoma syndrome which manifests predominantly with FH-deficient uterine/cutaneous leiomyomas and renal cell carcinomas (RCCs)-tumors characterized by loss of immunohistochemical (IHC) expression of FH and/or positive staining for S-(2-succino)-cysteine. Occasional patients develop PCC/PGL. We investigated the incidence, morphologic, and clinical features of FH-deficient PCC/PGL. We identified 589 patients with PCC/PGLs that underwent IHC screening for FH and/or S-(2-succino)-cysteine. Eight (1.4%) PCC/PGLs were FH deficient (1.1% in an unselected population). The median age for FH-deficient cases was 55 (range: 30 to 77 y) with 50% arising in the adrenal. All 4 with biochemical data were noradrenergic. Two (25%) metastasized, 1 dying of disease after 174 months. Germline testing was performed on 7 patients, 6 of whom had FH missense mutations. None were known to have a significant family history before presentation or developed cutaneous leiomyomas, or FH-deficient RCC at extended follow-up. The patient wild-type for FH on germline testing was demonstrated to have somatic FH mutation and loss of heterozygosity corresponding to areas of subclonal FH deficiency in her tumor. One patient did not undergo germline testing, but FH mutation was demonstrated in his tumor. We conclude that FH-deficient PCC/PGL are underrecognized but can be identified by IHC. FH-deficient PCC/PGL are strongly associated with germline missense mutations but are infrequently associated with leiomyoma or RCC, suggesting there may be a genotype-phenotype correlation. FH-deficient PCC/PGL may have a higher metastatic risk.
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Neoplasias das Glândulas Suprarrenais , Carcinoma de Células Renais , Neoplasias Renais , Leiomiomatose , Síndromes Neoplásicas Hereditárias , Paraganglioma , Feocromocitoma , Neoplasias Cutâneas , Neoplasias Uterinas , Feminino , Humanos , Neoplasias das Glândulas Suprarrenais/genética , Cisteína/análise , Fumarato Hidratase , Imuno-Histoquímica , Leiomiomatose/patologia , Síndromes Neoplásicas Hereditárias/patologia , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/patologia , Adulto , Pessoa de Meia-Idade , IdosoRESUMO
CONTEXT: Carriers of succinate dehydrogenase type B (SDHB) pathogenic variants (PVs) are at risk of pheochromocytoma and paraganglioma (PPGL) from a young age. It is widely recommended carriers enter a surveillance program to detect tumors, but there are limited studies addressing outcomes of surveillance protocols for SDHB PV carriers. OBJECTIVE: The purpose of this study was to describe surveillance-detected (s-d) tumors in SDHB PV carriers enrolled in a surveillance program and to compare their outcomes to probands. METHODS: This was a multicenter study of SDHB PV carriers with at least 1 surveillance episode (clinical, biochemical, imaging) in Australian genetics clinics. Data were collected by both retrospective and ongoing prospective follow-up. Median duration of follow-up was 6.0 years. RESULTS: 181 SDHB PV carriers (33 probands and 148 nonprobands) were assessed. Tumors were detected in 20% of nonprobands undergoing surveillance (age range 9-76 years). Estimated 10-year metastasis-free survival was 66% for probands and 84% for nonprobands with s-d tumors (Pâ =â .027). S-d tumors were smaller than those in probands (median 27 mm vs 45 mm respectively, Pâ =â .001). Tumor size ≥40 mm was associated with progression to metastatic disease (OR 16.9, 95% CI 2.3-187.9, Pâ =â .001). Patients with s-d tumors had lower mortality compared to probands: 10-year overall survival was 79% for probands and 100% for nonprobands (Pâ =â .029). CONCLUSION: SDHB carriers with s-d tumors had smaller tumors, reduced risk of metastatic disease, and lower mortality than probands. Our results suggest that SDHB PV carriers should undertake surveillance to improve clinical outcomes.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Adolescente , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Austrália/epidemiologia , Criança , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Mutação , Paraganglioma/diagnóstico , Paraganglioma/epidemiologia , Paraganglioma/genética , Estudos Prospectivos , Estudos Retrospectivos , Succinato Desidrogenase/genética , Adulto JovemRESUMO
Mosaic or somatic EPAS1 mutations are associated with a range of phenotypes including pheochromocytoma and/or paraganglioma (PPGL), polycythemia and somatostatinoma. The pathogenic potential of germline EPAS1 variants however is not well understood. We report a number of germline EPAS1 variants occurring in patients with PPGL, including a novel variant c.739C>A (p.Arg247Ser); a previously described variant c.1121T>A (p.Phe374Tyr); several rare variants, c.581A>G (p.His194Arg), c.2353C>A (p.Pro785Thr) and c.2365A>G (p.Ile789Val); a common variant c.2296A>C (p.Thr766Pro). We performed detailed functional studies to understand their pathogenic role in PPGL. In transient transfection studies, EPAS1/HIF-2α p.Arg247Ser, p.Phe374Tyr and p.Pro785Thr were all stable in normoxia. In co-immunoprecipitation assays, only the novel variant p.Arg247Ser showed diminished interaction with pVHL. A direct interaction between HIF-2α Arg247 and pVHL was confirmed in structural models. Transactivation was assessed by means of a HRE-containing reporter gene in transiently transfected cells, and significantly higher reporter activity was only observed with EPAS1/HIF-2α p.Phe374Tyr and p.Pro785Thr. In conclusion, three germline EPAS1 variants (c.739C>A (p.Arg247Ser), c.1121T>A (p.Phe374Tyr) and c.2353C>A (p.Pro785Thr)) all have some functional features in common with somatic activating mutations. Our findings suggest that these three germline variants are hypermorphic alleles that may act as modifiers to the expression of PPGLs.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Mutação em Linhagem Germinativa/genética , HumanosRESUMO
PURPOSE: This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). DESIGN: Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. MAIN OUTCOME ANALYSIS: Clinical, genetic, and functional associations were determined. RESULTS: The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P < .001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P < .001) and clustered disproportionately within transmembrane regions (P < .01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. CONCLUSIONS: Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.
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Neoplasias das Glândulas Suprarrenais/genética , Proteínas de Membrana/genética , Feocromocitoma/genética , Neoplasias das Glândulas Suprarrenais/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Feocromocitoma/epidemiologia , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Until recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional to their penetrance for disease. We tested this hypothesis using data from two cohorts for succinate dehydrogenase subunits A, B and C (SDHA-C) genetic variants associated with hereditary pheochromocytoma/paraganglioma (PC/PGL). METHODS: Two cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic SDHA-C variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas). RESULTS: Pathogenic SDHA-C variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 different pathogenic variants from both cohorts (seven in SDHA, 75 in SDHB and 12 in SDHC), 13 are reported in ExAC (two in SDHA, nine in SDHB and two in SDHC) accounting for 21% of subjects with SDHA-C variants. Combining data from both cohorts, estimated lifetime disease penetrance was 22.0% (95% CI 15.2% to 30.9%) for SDHB variants, 8.3% (95% CI 3.5% to 18.5%) for SDHC variants and 1.7% (95% CI 0.8% to 3.8%) for SDHA variants. CONCLUSION: Pathogenic variants in SDHB are more penetrant than those in SDHC and SDHA. Our findings have important implications for counselling and surveillance of subjects carrying these pathogenic variants.
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Teorema de Bayes , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Penetrância , Succinato Desidrogenase/genética , Algoritmos , Alelos , Austrália , Estudos de Associação Genética/métodos , Genótipo , Humanos , Isoenzimas , Modelos Genéticos , Fenótipo , Reino UnidoRESUMO
Pheochromocytomas (PC) and paragangliomas (PGL) are endocrine tumors for which the genetic and clinicopathological features of metastatic progression remain incompletely understood. As a result, the risk of metastasis from a primary tumor cannot be predicted. Early diagnosis of individuals at high risk of developing metastases is clinically important and the identification of new biomarkers that are predictive of metastatic potential is of high value. Activation of TERT has been associated with a number of malignant tumors, including PC/PGL. However, the mechanism of TERT activation in the majority of PC/PGL remains unclear. As TERT promoter mutations occur rarely in PC/PGL, we hypothesized that other mechanisms - such as structural variations - may underlie TERT activation in these tumors. From 35 PC and four PGL, we identified three primary PCs that developed metastases with elevated TERT expression, each of which lacked TERT promoter mutations and promoter DNA methylation. Using whole genome sequencing, we identified somatic structural alterations proximal to the TERT locus in two of these tumors. In both tumors, the genomic rearrangements led to the positioning of super-enhancers proximal to the TERT promoter, that are likely responsible for the activation of the normally tightly repressed TERT expression in chromaffin cells.
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Neoplasias das Glândulas Suprarrenais/genética , Biomarcadores Tumorais/genética , Mutação , Paraganglioma/genética , Feocromocitoma/genética , Regiões Promotoras Genéticas , Telomerase/genética , Neoplasias das Glândulas Suprarrenais/secundário , Metilação de DNA , Predisposição Genética para Doença , Humanos , Paraganglioma/patologia , Feocromocitoma/patologia , Prognóstico , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: Germline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with the development of pheochromocytoma (PC) and/or paraganglioma (PGL). As assembly factors have been identified as playing a role in maturation of individual SDH subunits and assembly of the functioning SDH complex, we hypothesized that SDHAF3 variants may be associated with PC/PGL and functionality of SDH. METHODS: DNA was extracted from the blood of 37 individuals (from 23 families) with germline SDH mutations and 18 PC/PGL (15 sporadic, 3 familial) and screened for mutations using a custom gene panel, containing SDHAF3 (SDH assembly factor 3) as well as eight known PC/PGL susceptibility genes. Molecular and functional consequences of an identified sequence variant of SDHAF3 were assessed in yeast and mammalian cells (HEK293). RESULTS: Using massively parallel sequencing, we identified a variant in SDHAF3, c.157 T > C (p.Phe53Leu), associated with increased prevalence in familial and sporadic PC/PGL (6.6%) when compared to normal populations (1.2% [1000 Genomes], p = 0.003; 2.1% [Exome Aggregation Consortium], p = 0.0063). In silico prediction tools suggest this variant is probably damaging to protein function, hence we assessed molecular and functional consequences of the resulting amino acid change (p.Phe53Leu) in yeast and human cells. We showed that introduction of SDHAF3 p.Phe53Leu into Sdh7 (ortholog of SDHAF3 in humans) null yeast resulted in impaired function, as observed by its failure to restore SDH activity when expressed in Sdh7 null yeast relative to WT SDHAF3. As SDHAF3 is involved in maturation of SDHB, we tested the functional impact of SDHAF3 c.157 T > C and various clinically relevant SDHB mutations on this interaction. Our in vitro studies in human cells show that SDHAF3 interacts with SDHB (residues 46 and 242), with impaired interaction observed in the presence of the SDHAF3 c.157 T > C variant. CONCLUSIONS: Our studies reveal novel insights into the biogenesis of SDH, uncovering a vital interaction between SDHAF3 and SDHB. We have shown that SDHAF3 interacts directly with SDHB (residue 242 being key to this interaction), and that a variant in SDHAF3 (c.157 T > C [p.Phe53Leu]) may be more prevalent in individuals with PC/PGL, and is hypomorphic via impaired interaction with SDHB.
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Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Paraganglioma/enzimologia , Feocromocitoma/enzimologia , Succinato Desidrogenase/metabolismo , Animais , Feminino , Células HEK293 , Humanos , Masculino , Simulação de Acoplamento Molecular , Paraganglioma/genética , Feocromocitoma/genética , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Mapeamento de Interação de Proteínas , Saccharomyces cerevisiae , Análise de Sequência de DNA , Succinato Desidrogenase/genética , Sus scrofa/metabolismoRESUMO
Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma and medullary thyroid cancer, are caused by autosomal dominant mutations in several familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours, or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion, but have undergone independent clonal evolution. Such tumours provide an opportunity to discover common cooperative changes required for tumourigenesis, while controlling for the genetic background of the individual. We performed genomic analysis of synchronous and metachronous tumours from five patients bearing germline mutations in the genes SDHB, RET, and MAX. Using whole exome sequencing and high-density single-nucleotide polymorphism arrays, we analysed two to four primary tumours from each patient. We also applied multi-region sampling, to assess intratumoural heterogeneity and clonal evolution, in two cases involving paraganglioma and medullary thyroid cancer, respectively. Heterogeneous patterns of genomic change existed between synchronous or metachronous tumours, with evidence of branching evolution. We observed striking examples of evolutionary convergence involving the same rare somatic copy-number events in synchronous primary phaeochromocytoma/paraganglioma. Convergent events also occurred during clonal evolution of metastatic medullary thyroid cancer. These observations suggest that genetic or epigenetic changes acquired early within precursor cells, or pre-existing within the genetic background of the individual, create contingencies that determine the evolutionary trajectory of the tumour. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Genes Neoplásicos/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Primárias Múltiplas/genética , Segunda Neoplasia Primária/genética , Tumores Neuroendócrinos/genética , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Exoma/genética , Feminino , Humanos , Perda de Heterozigosidade , Masculino , Neoplasias Primárias Múltiplas/patologia , Segunda Neoplasia Primária/patologia , Tumores Neuroendócrinos/patologia , Paraganglioma/genética , Feocromocitoma/genética , Feocromocitoma/patologia , Polimorfismo de Nucleotídeo Único/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Proteínas Proto-Oncogênicas c-ret/genética , Succinato Desidrogenase/genética , Adulto JovemRESUMO
OBJECTIVE: Mutations of genes encoding the four subunits of succinate dehydrogenase (SDH) have been associated with pheochromocytoma and paraganglioma (PPGLs), gastrointestinal stromal tumors (GISTs) and renal cell carcinomas (RCCs). These tumors have not been characterized in a way that reflects severity of SDH dysfunction. Mass spectrometric analysis now allows measurement of metabolites extracted from formalin fixed paraffin embedded (FFPE) specimens. We assess whether SDH deficiency in various tumor types characterized by loss of SDHB protein expression correlates with SDH dysfunction as assessed by the ratio of succinate:fumarate in FFPE specimens. PATIENTS AND METHODS: Sections of FFPE tumor specimens from 18 PPGL, 10 GIST and 11 RCC patients with known SDHx mutation status for SDH deficiency were collected for mass spectrometric analysis of succinate and fumarate. RESULTS: FFPE samples showed higher succinate:fumarate ratios in SDH-deficient PPGLs compared to SDH-sufficient PPGLs. Similarly, a higher succinate:fumarate ratio was able to distinguish SDH-deficient GISTs and RCCs from their SDH-sufficient counterparts with great selectivity. Interestingly, the cut-off value of the succinate:fumarate ratio was two-folds greater in RCCs than GISTs. CONCLUSION: Analyzing biochemical imbalances preserved in FFPE specimens with mass spectrometry expands the method and sample type repertoire available for characterisation of multiple neoplasias associated with SDH deficiency.
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Phaeochromocytomas and paragangliomas (PPGLs) are neural-crest-derived tumours of the sympathetic or parasympathetic nervous system that are often inherited and are genetically heterogeneous. Genetic testing is recommended for patients with these tumours and for family members of patients with hereditary forms of PPGLs. Due to the large number of susceptibility genes implicated in the diagnosis of inherited PPGLs, next-generation sequencing (NGS) technology is ideally suited for carrying out genetic screening of these individuals. This Consensus Statement, formulated by a study group comprised of experts in the field, proposes specific recommendations for the use of diagnostic NGS in hereditary PPGLs. In brief, the study group recommends target gene panels for screening of germ line DNA, technical adaptations to address different modes of disease transmission, orthogonal validation of NGS findings, standardized classification of variant pathogenicity and uniform reporting of the findings. The use of supplementary assays, to aid in the interpretation of the results, and sequencing of tumour DNA, for identification of somatic mutations, is encouraged. In addition, the study group launches an initiative to develop a gene-centric curated database of PPGL variants, with annual re-evaluation of variants of unknown significance by an expert group for purposes of reclassification and clinical guidance.
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Neoplasias das Glândulas Suprarrenais/diagnóstico , Conferências de Consenso como Assunto , Testes Genéticos/tendências , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Paraganglioma/genética , Feocromocitoma/genéticaRESUMO
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.
Assuntos
Neoplasias das Glândulas Suprarrenais/classificação , Neoplasias das Glândulas Suprarrenais/genética , Paraganglioma/classificação , Paraganglioma/genética , Feocromocitoma/classificação , Feocromocitoma/genética , Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Proteínas de Membrana/genética , Mutação , Neurofibromina 1/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA/análise , Succinato Desidrogenase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
The paraganglioma (PGL) syndromes types 1-5 are autosomal dominant disorders characterized by familial predisposition to PGLs, phaeochromocytomas (PCs), renal cell cancers, gastrointestinal stromal tumours and, rarely, pituitary adenomas. Each syndrome is associated with mutation in a gene encoding a particular subunit (or assembly factor) of succinate dehydrogenase (SDHx). The clinical manifestations of these syndromes are protean: patients may present with features of catecholamine excess (including the classic triad of headache, sweating and palpitations), or with symptoms from local tumour mass, or increasingly as an incidental finding on imaging performed for some other purpose. As genetic testing for these syndromes becomes more widespread, presymptomatic diagnosis is also possible, although penetrance of disease in these syndromes is highly variable and tumour development does not clearly follow a predetermined pattern. PGL1 syndrome (SDHD) and PGL2 syndrome (SDHAF2) are notable for high frequency of multifocal tumour development and for parent-of-origin inheritance: disease is almost only ever manifest in subjects inheriting the defective allele from their father. PGL4 syndrome (SDHB) is notable for an increased risk of malignant PGL or PC. PGL3 syndrome (SDHC) and PGL5 syndrome (SDHA) are less common and appear to be associated with lower penetrance of tumour development. Although these syndromes are all associated with SDH deficiency, few genotype-phenotype relationships have yet been established, and indeed it is remarkable that such divergent phenotypes can arise from disruption of a common molecular pathway. This article reviews the clinical presentations of these syndromes, including their component tumours and underlying genetic basis.
Assuntos
Síndromes Neoplásicas Hereditárias , Paraganglioma , Aconselhamento Genético , Testes Genéticos , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/terapiaRESUMO
Phaeochromocytomas (PCCs) and paragangliomas (PGLs) are rare neural crest-derived tumours originating from adrenal chromaffin cells or extra-adrenal sympathetic and parasympathetic tissues. More than a third of PCC/PGL cases are associated with heritable syndromes involving 13 or more known genes. These genes have been broadly partitioned into two groups based on pseudo-hypoxic and receptor tyrosine kinase (RTK) signalling pathways. Many of these genes can also become somatically mutated, although up to one third of sporadic cases have no known genetic driver. Furthermore, little is known of the genes that co-operate with known driver genes to initiate and drive tumourigenesis. To explore the genomic landscape of PCC/PGL, we applied exome sequencing, high-density SNP-array analysis, and RNA sequencing to 36 PCCs and four functional PGL tumours. All tumours displayed low mutation frequency, in contrast to frequent large segmental copy-number alterations, aneuploidy, and evidence for chromothripsis in one case. Multi-region sampling of one benign familial PCC tumour provided evidence for the timing of mutations during tumourigenesis and ongoing clonal evolution. Thirty-one of 40 (77.5%) cases could be explained by germline or somatic mutations or structural alterations affecting known PCC/PGL genes. Deleterious somatic mutations were also identified in known tumour-suppressor genes associated with genome maintenance and epigenetic modulation. A multitude of other genes were also found mutated that are likely important for normal neuroendocrine cell function. We revisited the gene-expression subtyping of PCC/PGL by integrating published microarray data with our RNA-seq data, enabling the identification of six robust gene-expression subtypes. The majority of cases in our cohort with no identifiable driver mutation were classified into a gene-expression subtype bearing similarity to MAX mutant PCC/PGL. Our data suggest there are yet unknown PCC/PGL cancer genes that can phenocopy MAX mutant PCC/PGL tumours. This study provides new insight into the molecular diversity and genetic origins of PCC/PGL tumours.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Predisposição Genética para Doença , Genômica , Paraganglioma/genética , Feocromocitoma/genética , Sequência de Bases , Exoma/genética , Humanos , Mutação/genética , Paraganglioma/diagnóstico , Feocromocitoma/diagnósticoRESUMO
BACKGROUND: Broad or general consent given by cancer patients for their tissue, blood, and clinical information to be stored in institutional biorepositories is fundamental to enable future ethical translational cancer research. The decision to consent for biobanking will contribute to the development of advanced diagnostic and prognostic tests, as well as new therapies to improve patient outcomes. While the rate of patient participation in biobanking programs is generally reported as high worldwide, few studies have investigated factors that may influence this decision. Biobanking at our medical research institute, an associated public (government-run) university hospital, and private hospital has been established for over 20 years, with collection of certain tumor types embedded in the research culture of these institutions. In this study, we investigated factors that may influence a cancer patient's decision to give broad consent for biobanking of their specimens. METHODS: Data on patient consent were collected over a 6-month period from both government and private hospitals associated with our medical research institute. Factors considered included gender, patient age at surgery, type of malignancy (breast, duodenal, cervical, endometrial, gastric, liver, esophageal, ovarian, pancreatic, pelvic, uterine, or vulval), type of institution where surgery was performed, and timing of consent. RESULTS: Of 171 cancer patients, 159 (93%) gave broad consent for biobanking of their tissue and blood specimens for future cancer research projects receiving ethical and scientific approval. None of the factors analyzed was shown to influence a patient's decision to contribute biological specimens and clinical data to a biorepository for future medical research. CONCLUSION: Biobanking for future ethically and scientifically approved research projects in an established institution is an initiative that receives strong support from patients undergoing cancer surgery, independent of factors including gender, age, type of tumor, type of institution where surgery was performed, or timing of consent.
Assuntos
Bancos de Espécimes Biológicos , Consentimento Livre e Esclarecido , Neoplasias/patologia , Adulto , Feminino , Humanos , MasculinoRESUMO
Succinate dehydrogenase (SDH)-deficient renal carcinoma has been accepted as a provisional entity in the 2013 International Society of Urological Pathology Vancouver Classification. To further define its morphologic and clinical features, we studied a multi-institutional cohort of 36 SDH-deficient renal carcinomas from 27 patients, including 21 previously unreported cases. We estimate that 0.05% to 0.2% of all renal carcinomas are SDH deficient. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M:F=1.7:1). Bilateral tumors were observed in 26% of patients. Thirty-four (94%) tumors demonstrated the previously reported morphology at least focally, which included: solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, and round to oval low-grade nuclei. All 17 patients who underwent genetic testing for mutation in the SDH subunits demonstrated germline mutations (16 in SDHB and 1 in SDHC). Nine of 27 (33%) patients developed metastatic disease, 2 of them after prolonged follow-up (5.5 and 30 y). Seven of 10 patients (70%) with high-grade nuclei metastasized as did all 4 patients with coagulative necrosis. Two of 17 (12%) patients with low-grade nuclei metastasized, and both had unbiopsied contralateral tumors, which may have been the origin of the metastatic disease. In conclusion, SDH-deficient renal carcinoma is a rare and unique type of renal carcinoma, exhibiting stereotypical morphologic features in the great majority of cases and showing a strong relationship with SDH germline mutation. Although this tumor may undergo dedifferentiation and metastasize, sometimes after a prolonged delay, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis.
Assuntos
Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/patologia , Neoplasias Renais/enzimologia , Neoplasias Renais/patologia , Succinato Desidrogenase/biossíntese , Adolescente , Adulto , Idoso , Carcinoma de Células Renais/genética , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Succinato Desidrogenase/genética , Análise Serial de Tecidos , Adulto JovemRESUMO
Germline mutations in the succinate dehydrogenase genes (SDHA, SDHB, SDHC, and SDHD) are established as causes of pheochromocytoma/paraganglioma, renal carcinoma, and gastrointestinal stromal tumor. It has recently been suggested that pituitary adenomas may also be a component of this syndrome. We sought to determine the incidence of SDH mutation in pituitary adenomas. We performed screening immunohistochemistry for SDHB and SDHA on all available pituitary adenomas resected at our institution from 1998 to 2012. In those patients with an abnormal pattern of staining, we then performed SDH mutation analysis on DNA extracted from paraffin-embedded tissue, fresh frozen tissue, and peripheral blood. One of 309 adenomas (0.3%) demonstrated an abnormal pattern of staining, a 30 mm prolactin-producing tumor from a 62-year-old man showing loss of staining for both SDHA and SDHB. Examination of paraffin-embedded and frozen tissues confirmed double-hit inactivating somatic SDHA mutations (c.725_736del and c.989_990insTA). Neither of these mutations was present in the germline. We conclude that, although pathogenic SDH mutation may occur in pituitary adenomas and can be identified by immunohistochemistry, it appears to be a very rare event and can occur in the absence of germline mutation. SDH-deficient pituitary adenomas may be larger and more likely to produce prolactin than other pituitary adenomas. Unless suggested by family history and physical examination, it is difficult to justify screening for SDH mutations in pituitary adenomas. Surveillance programs for patients with SDH mutation may be tailored to include the possibility of pituitary neoplasia; however, this is likely to be a low-yield strategy.