The genetic basis of pheochromocytoma and paraganglioma: implications for management.
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ABSTRACT:
SUBMITTER: Shuch B
PROVIDER: S-EPMC4572836 | biostudies-literature | 2014 Jun
REPOSITORIES: biostudies-literature
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The genetic basis of pheochromocytoma and paraganglioma: implications for management.
Shuch Brian B Ricketts Christopher J CJ Metwalli Adam R AR Pacak Karel K Linehan W Marston WM
Urology 20140315 6
Chromaffin cells are catecholamine-producing cells derived from neural crest tissue. Chromaffin tumors are rare tumors arising from these cells and are divided into pheochromocytoma arising from adrenal tissue and paraganglioma arising from extra-adrenal ganglia. Previously, ∼10% were believed to be hereditary, but advances in genome sequencing have shown that roughly 35% of apparently sporadic tumors have a hereditary component. In this review, we describe both classic and newly discovered here ...[more]
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Project description:Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters based on underlying genetic alterations. With around 30% to 35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35% to 40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to 1 of 3 main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling-related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling-related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and provide personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan.
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Project description:Pheochromocytomas and paragangliomas (PPGLs) are rare catecholamine-secreting neuroendocrine tumors of the adrenal medulla and sympathetic/parasympathetic ganglion cells, respectively. Excessive release of catecholamines leads to episodic symptoms and signs of PPGL, which include hypertension, headache, palpitations, and diaphoresis. Intraoperatively, large amounts of catecholamines are released into the bloodstream through handling and manipulation of the tumor(s). In contrast, there could also be an abrupt decline in catecholamine levels after tumor resection. Because of such binary manifestations of PPGL, patients may develop perplexing and substantially devastating cardiovascular complications during the perioperative period. These complications include hypertension, hypotension, arrhythmias, myocardial infarction, heart failure, and cerebrovascular accident. Other complications seen in the postoperative period include fever, hypoglycemia, cortisol deficiency, urinary retention, etc. In the interest of safe patient care, such emergencies require precise diagnosis and treatment. Surgeons, anesthesiologists, and intensivists must be aware of the clinical manifestations and complications associated with a sudden increase or decrease in catecholamine levels and should work closely together to be able to provide appropriate management to minimize morbidity and mortality associated with PPGLs.
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Project description:Despite all technical progress in modern diagnostic methods and treatment modalities of pheochromocytoma/paraganglioma, early consideration of the presence of these tumors remains the pivotal link towards the best possible outcome for patients. A timely diagnosis and proper treatment can prevent the wide variety of potentially catastrophic cardiovascular complications. Modern biochemical testing should include tests that offer the best available diagnostic performance, measurements of metanephrines and 3-methoxytyramine in plasma or urine. To minimize false-positive test results particular attention should be paid to pre-analytical sampling conditions. In addition to anatomical imaging by computed tomography (CT) or magnetic resonance imaging, new promising functional imaging modalities of photon emission tomography/CT using with somatostatin analogues such as ⁶⁸Ga-DOTATATE (⁶⁸Ga-labeled DOTA(0)-Tyr(3)-octreotide) will probably replace ¹²³I-MIBG (iodine-123-metaiodobenzylguanidine) in the near future. As nearly half of all pheochromocytoma patients harbor a mutation in one of the 14 tumor susceptibility genes, genetic testing and counseling should at least be considered in all patients with a proven tumor. Post-surgical annual follow-up of patients by measurements of plasma or urinary metanephrines should last for at least 10 years for timely detection of recurrent or metastatic disease. Patients with a high risk for recurrence or metastatic disease (paraganglioma, young age, multiple or large tumors, genetic background) should be followed up lifelong.
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Project description:Pheochromocytoma and paragangliomas (PPGLs) are rare neuroendocrine tumors carrying 25-40% pathogenic germline gene variants (PGVs). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (14 patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remaining had samples submitted to complete next-generation sequencing aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, and VHL. We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclusively pathogenic or likely pathogenic variants, 13 (19.4%) had pathogenic or likely pathogenic variants and variant of undetermined significance (VUS), and 20 (29.8%) carried only VUS. PGVs were found in RET (n = 18; 38.3%), VHL (n = 10; 21.3%), SDHB and NF1 (n = 8; 17% each), and MAX, SDHD, TMEM127, and TP53 (n = 1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive predictive value (PPV) and negative predictive values (NPV), respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs.
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Project description:Pheochromocytomas and paragangliomas (PCC/PGL) are tumors derived from the adrenal medulla or extra-adrenal ganglia, respectively. They are rare and often benign tumors that are associated with high morbidity and mortality due to mass effect and high circulating catecholamines. Although most PCCs and PGLs are thought to be sporadic, over one third are associated with 10 known susceptibility genes. Mutations in three genes causing well characterized tumor syndromes are associated with an increased risk of developing PCCs and PGLs, including VHL (von Hippel-Lindau disease), NF1 (Neurofibromatosis Type 1), and RET (Multiple Endocrine Neoplasia Type 2). Mutations in any of the succinate dehydrogenase (SDH) complex subunit genes (SDHA, SDHB, SDHC, SDHD) can lead to PCCs and PGLs with variable penetrance, as can mutations in the subunit cofactor, SDHAF2. Recently, two additional genes have been identified, TMEM127 and MAX. Although these tumors are rare in the general population, occurring in two to eight per million people, they are more commonly associated with an inherited mutation than any other cancer type. This review summarizes the known germline and somatic mutations leading to the development of PCC and PGL, as well as biochemical profiling for PCCs/PGLs and screening of mutation carriers.
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Project description:Cyclooxygenase 2 (COX-2) is a key enzyme of the tumorigenesis-inflammation interface and can be induced by hypoxia. A pseudohypoxic transcriptional signature characterizes pheochromocytomas and paragangliomas (PPGLs) of the cluster I, mainly represented by tumors with mutations in von Hippel-Lindau (VHL), endothelial PAS domain-containing protein 1 (EPAS1), or succinate dehydrogenase (SDH) subunit genes. The aim of this study was to investigate a possible association between underlying tumor driver mutations and COX-2 in PPGLs. COX-2 gene expression and immunoreactivity were examined in clinical specimens with documented mutations, as well as in spheroids and allografts derived from mouse pheochromocytoma (MPC) cells. COX-2 in vivo imaging was performed in allograft mice. We observed significantly higher COX-2 expression in cluster I, especially in VHL-mutant PPGLs, however, no specific association between COX-2 mRNA levels and a hypoxia-related transcriptional signature was found. COX-2 immunoreactivity was present in about 60% of clinical specimens as well as in MPC spheroids and allografts. A selective COX-2 tracer specifically accumulated in MPC allografts. This study demonstrates that, although pseudohypoxia is not the major determinant for high COX-2 levels in PPGLs, COX-2 is a relevant molecular target. This potentially allows for employing selective COX-2 inhibitors as targeted chemotherapeutic agents and radiosensitizers. Moreover, available models are suitable for preclinical testing of these treatments.
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Project description:Background and aimsPheochromocytomas (PCCs) and Paragangliomas (PGL) are rare catecholamine producing tumors that may present in sporadic or familial settings. Despite vast strides in understanding of PCC/PGL genetics in the last two decades, there is a dearth of information from India. The aim here is to study the prevalence of genetic mutations in Indian PCC/PGL patients.Settings and designTertiary care academic hospital; prospective study.Methods50 histopathologically diagnosed PCC/PGL patients formed the study group. Clinical, biochemical, pathological attributes and outcomes were documented and the phenotype was compared to the genotype. Succinyl dehydrogenase (SDH), Re-Arranged during Transfection (RET), Von-Hippel-Lindau (VHL) and NeuroFibromatosis-1 (NF1) mutations were studied. Additionally, immunohistochemisty for SDHB was also done, and the results compared to mutational analysis of SDH by MLPA (Multiplex Ligation-dependent Probe Activation).Statistical analysisIndependent samples t-test and Fisher's exact test were used as appropriate. P values ≤0.05 were considered statistically significant.ResultsThe mean age was 34.3 years. Of the 50 patients, 27 were males and 23 females. 10 patients (20%) in all were detected to have a genetic mutation. 6 patients possessed a RET mutation, while two had VHL mutations. No patient presented with a NF1 mutation. 2 patients had a SDH mutation, and Immunohistochemistry for SDHB correlated with mutational analysis for these patients.ConclusionsThe proportion of patients with a familial variant of PCC/PGL is more than what the historic "Rule of Ten" suggests. Our study found that one in five patients have a genetic mutation. PCC/PGL patients with genetic mutations not only require more stringent follow-up, but also screening of family members.
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Project description:BackgroundPheochromocytoma and paragangliomas (PPGL) are known as tumors with the highest level of heritability, approximately 30% of all cases. Clinical practice guidelines of PPGL recommend genetic testing for germline variants in all patients. In this study, we used whole exome sequencing to identify novel causative variants associated with PPGL to improve the detection of rare genetic variants in our cohort.MethodsThirty-six tested negative for pathogenic variants in previous Sanger sequencing or targeted gene panel testing for PPGL underwent whole exome sequencing. Whole exome sequencing was performed using DNA samples enriched using TruSeq Custom Enrichment Kit and sequenced with MiSeq (Illumina Inc.). Sequencing alignment and variant calling were performed using SAMtools.ResultsAmong previously mutation undetected 36 patients, two likely pathogenic variants and 13 variants of uncertain significance (VUS) were detected in 32 pheochromocytoma-related genes. SDHA c.778G>A (p.Gly260Arg) was detected in a patient with head and neck paraganglioma, and KIF1B c.2787-2A>C in a patient with a bladder paraganglioma. Additionally, a likely pathogenic variant in BRCA2, VUS in TP53, and VUS in NFU1 were detected.ConclusionExome sequencing further identified genetic alterations by 5.6% in previously mutation undetected patients in PPGL. Implementation of targeted gene sequencing consisted of extended genes of PPGL in routine clinical screening can support the level of comprehensive patient assessment.
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Project description:Pheochromocytoma/paraganglioma (PPGL) has a high genetic heterogeneity with 40% germline variants in known pathogenic genes. Data in Chinese on this aspect are scanty. To detect the genetic and clinical profile of Chinese PPGL patients, we examined the variants of 12 known germline pathogenic genes (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, RET, NF1, MAX, TMEM127, and KIF1B) by next-generation sequencing and Sanger sequencing in 314 Chinese PPGL subjects. Twenty nine percent of Chinese PPGL patients had germline variants and SDHB was the most frequently mutated (14.6%). The most frequent SDHB variants were in exon 2, exon 7, and IVS 7. Pathogenic variants were more likely to occur in metastatic PPGL patients, paragangliomas, and patients under 30, with the ratio being 50.7% (35/69), 35.9% (56/156), and 49.5% (52/105), respectively. Our cohort included 314 patients from a single setting. The genetic and clinical features of Chinese PPGL patients were unique in some aspects compared to their non-Chinese counterparts. Identification of genotype-phenotype relation can serve as an effective tool for genetic prioritization and clinical decision-making.
| S-EPMC7761866 | biostudies-literature
Project description:Fibroblast growth factor 21 (FGF21) is a hepatokine with beneficial effects on metabolism. Our aim was to evaluate the relationship between the serum FGF21, and energy and glucose metabolism in 40 patients with pheochromocytoma/functional paraganglioma (PPGL), in comparison with 21 obese patients and 26 lean healthy controls. 27 patients with PPGL were examined one year after tumor removal. Basic anthropometric and biochemical measurements were done. Energy metabolism was measured by indirect calorimetry (Vmax-Encore 29N). FGF21 was measured by ELISA. FGF21 was higher in PPGL than in controls (174.2 (283) pg/mL vs. 107.9 (116) pg/mL; p < 0.001) and comparable with obese (174.2 (283) pg/mL vs. 160.4 (180); p = NS). After tumor removal, FGF21 decreased (176.4 (284) pg/mL vs. 131.3 (225) pg/mL; p < 0.001). Higher levels of FGF21 were expressed, particularly in patients with diabetes. FGF21 positively correlated in PPGL with age (p = 0.005), BMI (p = 0.028), glycemia (p = 0.002), and glycated hemoglobin (p = 0.014). In conclusion, long-term catecholamine overproduction in PPGL leads to the elevation in serum FGF21, especially in patients with secondary diabetes. FGF21 levels were comparable between obese and PPGL patients, despite different anthropometric indices. We did not find a relationship between FGF21 and hypermetabolism in PPGL. Tumor removal led to the normalization of FGF21 and the other metabolic abnormalities.
| S-EPMC6520899 | biostudies-literature