Genetics of Pheochromocytoma and Paraganglioma

Pereira, Bernardo Dias; Luiz, Henrique Vara; Ferreira, Ana Paula Bonilauri; Portugal, Jorge

doi:10.15586/paraganglioma.2019.ch1

Cited by 9 publications

(5 citation statements)

References 117 publications

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“…Furthermore, high 2′-deoxy-ATP/ATP ratios and dAdo availability could facilitate the synthesis of adenosine 2′-diphosphoribose, an endogenous superagonist of the transient receptor potential (TRP) melastatin 2 (TRPM2) plasma membrane cation channel that, under ROS-induced stress, controls Ca2+ fluxes and hence Ca2+ signaling, mitochondrial respiratory uncoupling and immune function (48-50). Sustained Ca2+ influx and oxidative stress rapidly reach a cytotoxic and apoptotic threshold in normal cells, but in HNPGL cells, where alternative metabolism implies enhanced anti-oxidant capacity and reduced dependence on the mitochondrial electron transport chain, ROS exposure activates key transcription factors, most notably HIF2A/EPAS1, whose downstream targets support tumor cell survival and proliferation in presence of dysfunctional mitochondria (1)(2)(3)39,40,51,52).…”

Section: Discussionmentioning

confidence: 99%

“…ROC analyses obtained with different numbers of metabolites (2,3,4,5,6,7,8,9,10) always yielded a large area under the curve (AUC), indicating ability to distinguish between diagnostic groups (Figure 4). The best confusion matrix obtained from the ROC curve based on 2 metabolites, dAdo and C26:0-LPC, provided a measure of classification accuracy, detecting correct and incorrect predictions for class after cross-validation.…”

Section: Putative Hnpgl Biomarkers a Roc Curve-based Multivariate Ana...mentioning

confidence: 99%

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Targeted metabolomics detects a putatively diagnostic signature in plasma and dried blood spots from head and neck paraganglioma patients

Verginelli¹,

Fabritiis²,

Valentinuzzi³

et al. 2022

Preprint

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Head and neck paragangliomas (HNPGLs), rare radio/chemo-resistant tumors curable only with surgery, are strongly influenced by genetic predisposition, hence patients and relatives require lifetime follow-up with MRI and/or PET-CT because of de novo disease risk. This entails exposure to electromagnetic/ionizing radiation, costs, and organizational challenges, because patients and relatives are scattered far from reference centers. Simplified first-line screening strategies are needed. We employed flow injection analysis tandem mass spectrometry, as used in newborn metabolic screening, to compare the plasma metabolic profile of HNPGL patients (59 samples, 56 cases) and healthy controls (24 samples, 24 cases). Principal Component Analysis (PCA) and Partial Least Discriminant Analysis (PLS-DA) highlighted a distinctive HNPGL signature, likely reflecting anaplerotic conversion of the TCA cycle to glutaminolysis and catabolism of branched amino acids, DNA damage and deoxyadenosine (dAdo) accumulation, impairment of fatty acid oxidation, switch towards the Warburg effect and proinflammatory lysophosphatidylcholines (LPCs) signaling. Statistical analysis of the metabolites that most impacted on PLS-DA was extended to 10 acoustic neuroma and 2 cholesteatoma patients, confirming significant differences relative to the HNPGL plasma metabolomic profile. The best confusion matrix from the ROC curve built on 2 metabolites, dAdo and C26:0-LPC, provided respective specificities of 94.29% and 89.29% and predictive powers of 96.15% and 84.62%. Analysis of dAdo and C26:0-LPC levels in dried venous and capillary blood confirmed that dAdo, likely deriving from 2′-deoxy-ATP accumulated in HNPGL cells following endogenous genotoxic damage, efficiently discriminated HNPGL patients from healthy controls and acoustic neuroma/cholesteatoma patients on easily manageable dried blood spots.

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Section: Discussionmentioning

confidence: 99%

Section: Putative Hnpgl Biomarkers a Roc Curve-based Multivariate Ana...mentioning

confidence: 99%

Targeted metabolomics detects a putatively diagnostic signature in plasma and dried blood spots from head and neck paraganglioma patients

Verginelli¹,

Fabritiis²,

Valentinuzzi³

et al. 2022

Preprint

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“…They have a strong genetic background and originate either in the adrenal medulla (80%) or in the sympathetic or parasympathetic paraganglia (20%), "extra-adrenal pheochromocytomas" (paraganglioma) as formerly referred to in [2]. A considerable proportion (40%) of pheocromocytoma/paraganglioma (PPGL) is diagnosed as manifestations of hereditary tumor syndromes, including familial paraganglioma syndrome types 1-5 (mutations in genes coding for subunits and associated factors of succinate dehydrogenase (SDH), e.g., SDHB, SDHC, SDHD, SDHA and SDHAF2 (collectively called SDHx), von Hippel-Lindau syndrome (mutations of VHL tumor suppressor), multiple endocrine neoplasia type 2 (mutations of the RET protooncogene), neurofibromatosis type 1 (mutations of NF1 tumor suppressor) and other germline mutations of various genes linked to major pathogenic processes in PPGL pathogenesis (e.g., HIF2A, MAX, MDH2, FH, TMEM127, KIF1B, PHD/EGLN1) [3][4][5]. At present, there are more than 12 genetic syndromes and 22 PPGL driver genes that contribute to PPGL formation [6,7].…”

Section: Of 16mentioning

confidence: 99%

MicroRNAs, Long Non-Coding RNAs, and Circular RNAs: Potential Biomarkers and Therapeutic Targets in Pheochromocytoma/Paraganglioma

Turai

Nyírő²,

Butz

et al. 2021

Cancers

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Around 40% of pheochromocytomas/paragangliomas (PPGL) harbor germline mutations, representing the highest heritability among human tumors. All PPGL have metastatic potential, but metastatic PPGL is overall rare. There is no available molecular marker for the metastatic potential of these tumors, and the diagnosis of metastatic PPGL can only be established if metastases are found at “extra-chromaffin” sites. In the era of precision medicine with individually targeted therapies and advanced care of patients, the treatment options for metastatic pheochromocytoma/paraganglioma are still limited. With this review we would like to nurture the idea of the quest for non-coding ribonucleic acids as an area to be further investigated in tumor biology. Non-coding RNA molecules encompassing microRNAs, long non-coding RNAs, and circular RNAs have been implicated in the pathogenesis of various tumors, and were also proposed as valuable diagnostic, prognostic factors, and even potential treatment targets. Given the fact that the pathogenesis of tumors including pheochromocytomas/paragangliomas is linked to epigenetic dysregulation, it is reasonable to conduct studies related to their epigenetic expression profiles and in this brief review we present a synopsis of currently available findings on the relevance of these molecules in these tumors highlighting their diagnostic potential.

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“…These tumors are usually benign and the 10-year overall survival is around ~96%, but 10% of PCC and even 40% of PGL occur as metastatic disease resulting in a 5-year survival below 50% [ 122 ]. Interestingly, PPGL has an extremely high rate of genetic susceptibility, when a germline mutation leads to autosomal dominant genetic syndromes (multiple endocrine neoplasia type 2A and 2B caused by RET mutations, von Hippel Lindau syndrome due to VHL mutations, neurofibromatosis type 1 with NF1 mutations or hereditary PG syndrome caused by mutations of succinate dehydrogenase (SDH) genes, PPGL genes including KIF1b , PHD2 , TMEM127 , MAX , FH , MDH2 , GOT2 and SLC25A11 [ 123 ]. Unfortunately, there are neither clear histopathological signs of malignant behavior or efficient therapy for malignant PPGL.…”

Section: Mirnas In Endocrine Tumorsmentioning

confidence: 99%

Essential Role of the 14q32 Encoded miRNAs in Endocrine Tumors

Krokker

Patócs

Butz

2021

Genes

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Background: The 14q32 cluster is among the largest polycistronic miRNA clusters. miRNAs encoded here have been implicated in tumorigenesis of multiple organs including endocrine glands. Methods: Critical review of miRNA studies performed in endocrine tumors have been performed. The potential relevance of 14q32 miRNAs through investigating their targets, and integrating the knowledge provided by literature data and bioinformatics predictions have been indicated. Results: Pituitary adenoma, papillary thyroid cancer and a particular subset of pheochromocytoma and adrenocortical cancer are characterized by the downregulation of miRNAs encoded by the 14q32 cluster. Pancreas neuroendocrine tumors, most of the adrenocortical cancer and medullary thyroid cancer are particularly distinct, as 14q32 miRNAs were overexpressed. In pheochromocytoma and growth-hormone producing pituitary adenoma, however, both increased and decreased expression of 14q32 miRNAs cluster members were observed. In the background of this phenomenon methodological, technical and biological factors are hypothesized and discussed. The functions of 14q32 miRNAs were also revealed by bioinformatics and literature data mining. Conclusions: 14q32 miRNAs have a significant role in the tumorigenesis of endocrine organs. Regarding their stable expression in the circulation of healthy individuals, further investigation of 14q32 miRNAs could provide a potential for use as biomarkers (diagnostic or prognostic) in endocrine neoplasms.

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Genetics of Pheochromocytoma and Paraganglioma

Cited by 9 publications

References 117 publications

Targeted metabolomics detects a putatively diagnostic signature in plasma and dried blood spots from head and neck paraganglioma patients

Targeted metabolomics detects a putatively diagnostic signature in plasma and dried blood spots from head and neck paraganglioma patients

MicroRNAs, Long Non-Coding RNAs, and Circular RNAs: Potential Biomarkers and Therapeutic Targets in Pheochromocytoma/Paraganglioma

Essential Role of the 14q32 Encoded miRNAs in Endocrine Tumors

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