Materiały źródłowe

• #1 Epidemiology, clinical presentation, and diagnosis of paragangliomas – UpToDate

  https://www.uptodate.com/contents/epidemiology-clinical-presentation-and-diagnosis-of-paragangliomas

  Paragangliomas are rare neuroendocrine tumors that arise from the extra-adrenal autonomic paraganglia, small organs consisting mainly of neuroendocrine cells that are derived from the embryonic neural crest and have the ability to secrete catecholamines. […] Some hereditary paragangliomas, particularly those arising in the skull base and neck, have been linked to pathogenic variants in the genes encoding different subunits of the succinate dehydrogenase (SDH) enzyme complex. […] This topic review will cover the epidemiology, risk factors, molecular pathogenesis, histology, clinical manifestations, diagnosis, and genetic screening issues of paragangliomas arising at a variety of sites in the body.

• #2 Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity | Nature Reviews Cancer

  https://www.nature.com/articles/nrc3648

  Pheochromocytomas and paragangliomas carry the highest degree of heritability (around 40%) of all human tumours and thus represent relevant models for the identification of driver mutations in cancer. […] More than 12 genes, belonging to a wide range of functional classes are mutated in the germ line or, less frequently, in somatic pheochromocytomas and paragangliomas, but many tumours remain genetically undefined. […] Mechanisms involved in the malignant transformation of pheochromocytomas and paragangliomas are not fully elucidated, and treatment options for these tumours are still limited. […] Mutations of metabolism genes uncovered the cell growth-promoting effects of metabolism intermediates (succinate) through epigenetic (histone and DNA methylation) modulation and activation of a hypoxic response.

• #3 Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. | EBSCOhost

  http://search.ebscohost.com/login.aspx?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=1474175X&asa=Y&AN=93922496&h=oJXKfKp0sYDTaMtrKPiy%2FdialsTyMSAgwxl8Y%2Fu6ZE4bwr3%2Fm0%2BMFEgzN2%2B%2Bxi1vW3IDdMsuUo8VVjcgccfgYw%3D%3D&crl=c

  The neuroendocrine tumours pheochromocytomas and paragangliomas carry the highest degree of heritability in human neoplasms, enabling genetic alterations to be traced to clinical phenotypes through their transmission in families. […] Mutations in more than a dozen distinct susceptibility genes have implicated multiple pathways in these tumours, offering insights into kinase downstream signalling interactions and hypoxia regulation, and uncovering links between metabolism, epigenetic remodelling and cell growth. […] Hereditary pheochromocytomas and paragangliomas are powerful models for recognizing cancer driver events, which can be harnessed for diagnostic purposes and for guiding the future development of targeted therapies.

• #4 Paraganglioma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549834/

  Pathogenic mutations in SDHx lead to 5 autosomal dominant hereditary paraganglioma syndromes. […] Recent data indicates that hypoxia-inducible factors (HIFs) may play a role in the genesis of paragangliomas in specific cases. […] Individuals with variants in the VHL and SDHx genes exhibit a pseudohypoxic response, leading to the stabilization, dysregulation, and overexpression of HIFs. […] Tumors with pathogenic variants in the VHL gene closely resemble those with variants in the SDHx genes. […] Shared characteristics of both VHL and SDHx variants include angiogenesis, hypoxia, and a diminished oxidative response, suggesting a common molecular pathway in the development of these tumors. […] The primary pathophysiology underlying a paraganglioma involves either the excessive secretion of catecholamines or bony erosion due to mass effect.

• #5 Paraganglioma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549834/

  Paragangliomas cause episodic secretion of catecholamines, leading to symptoms of catecholamine excess. […] Parasympathetic paragangliomas located in the skull base are usually non-secretory, with less than 5% secreting catecholamines and becoming symptomatic. […] Histologically, paragangliomas and pheochromocytomas are nearly identical, differing primarily in the presence of chromaffin cells. […] The gross specimen is firm, rubbery, and brown, with a central scar and a thin capsule. […] Clinicians gain minimal prognostic information, risk of recurrence, or metastases from pathologic evaluations alone. […] Approximately 20% of extra-adrenal paragangliomas are malignant, while 10% of pheochromocytomas are malignant. […] The surgical approach to these tumors depends mainly on the location, size, and body habitus of the patient.

• #6 New insights on the pathogenesis of paraganglioma… | F1000Research

  https://f1000research.com/articles/7-1500

  Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare chromaffin cell tumors (PPGLs) that at times raise significant challenges in clinical recognition, diagnosis, and therapy and when undiagnosed could associate with severe morbidity. Recent discoveries in PPGL genetics propelled our understanding in the pathophysiology of tumorigenesis and allowed the application of functional classification of pathogenetically distinct groups of PPGLs. […] Establishment of the fact that mutations in multiple components of the PHDVHLHIF-2 pathway associate with pseudohypoxia-driven tumorigenesis allowed us not only to better understand the effect of this phenomenon but also to more deeply appreciate the value of functional abnormalities in the physiologic tissue oxygen-sensing mechanism. […] The importance of the PHDVHLHIF-2 pathway in the pathogenesis of PPGL was also shown through the association of mutations in every component of this pathway.

• #7 SciELO Brazil – The clinical genetics of phaeochromocytoma and paraganglioma The clinical genetics of phaeochromocytoma and paraganglioma

  https://www.scielo.br/j/aem/a/vmp3S83tXqvLVqJz64Zr3Mb/

  The pathogenesis of the hereditary nature of phaeochromocytoma can be described in two main clusters. The first cluster contains pseudohypoxia-driven tumours including VHL, SDH, EGLN1 and HIF2A mutant tumours. The second cluster contained the kinase signalling subgroup including the RET, NF1, TMEM 127 and MAX mutant tumours. […] The feature common to all cluster 1 tumours is the activation of HIFs. Hypoxia inducible factors (HIFs) are transcription factors induced as a physiological response to cellular hypoxia. In the presence of VHL, SDH, EGLN1 and HIF2A mutations, HIFs are induced and stabilised, pointing the cell towards a pseudo-hypoxic state. Pseudohypoxia occurs when HIF pathways are constitutively activated, regardless of oxygen levels. This cellular pseudohypoxia leads to epigenetic modifications in HIF target genes affecting multiple cellular processes including apoptosis, angiogenesis, proliferation, migration, and invasion.

• #8 Paraganglioma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549834/

  Pathogenic mutations in SDHx lead to 5 autosomal dominant hereditary paraganglioma syndromes. […] Recent data indicates that hypoxia-inducible factors (HIFs) may play a role in the genesis of paragangliomas in specific cases. […] Individuals with variants in the VHL and SDHx genes exhibit a pseudohypoxic response, leading to the stabilization, dysregulation, and overexpression of HIFs. […] Tumors with pathogenic variants in the VHL gene closely resemble those with variants in the SDHx genes. […] Shared characteristics of both VHL and SDHx variants include angiogenesis, hypoxia, and a diminished oxidative response, suggesting a common molecular pathway in the development of these tumors. […] The primary pathophysiology underlying a paraganglioma involves either the excessive secretion of catecholamines or bony erosion due to mass effect.

• #9 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations in: Endocrine-Related Cancer Volume 22 Issue 4 (2015)

  https://erc.bioscientifica.com/view/journals/erc/22/4/T71.xml

  Recent genome-wide expression profiling studies show strong induction of hypoxia and angiogenesis pathways in SDH- and VHL-related PPGL. SDH and VHL mutations induce both protein encoding mRNAs and miRNAs (miR-210) that are implicated in cellular adaptation to hypoxia. Although certain differences in the induced genes were observed, the broad overlap amongst the hypoxia induced genes between SDH- and VHL-related paragangliomas strongly suggest that pathogenesis of SDH tumors involves constitutive hypoxic stimulation. […] Broad transcriptional overlap between SDH and VHL-related PPGL, and constitutive activation of the HIFs in VHL suggested that HIFs may also mediate tumor formation in SDH-mutated paragangliomas. HIF1 and/or HIF2 were detected by immunohistochemistry in both SDH-mutated and sporadic HNPGL. In vitro studies using cell lines showed that siRNA-mediated knockdown of SDH subunits led to stabilization of HIF1. These studies linked increased succinate or ROS levels to the stabilization of HIFs.

• #10 Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. | EBSCOhost

  http://search.ebscohost.com/login.aspx?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=1474175X&asa=Y&AN=93922496&h=oJXKfKp0sYDTaMtrKPiy%2FdialsTyMSAgwxl8Y%2Fu6ZE4bwr3%2Fm0%2BMFEgzN2%2B%2Bxi1vW3IDdMsuUo8VVjcgccfgYw%3D%3D&crl=c

  The neuroendocrine tumours pheochromocytomas and paragangliomas carry the highest degree of heritability in human neoplasms, enabling genetic alterations to be traced to clinical phenotypes through their transmission in families. […] Mutations in more than a dozen distinct susceptibility genes have implicated multiple pathways in these tumours, offering insights into kinase downstream signalling interactions and hypoxia regulation, and uncovering links between metabolism, epigenetic remodelling and cell growth. […] Hereditary pheochromocytomas and paragangliomas are powerful models for recognizing cancer driver events, which can be harnessed for diagnostic purposes and for guiding the future development of targeted therapies.

• #11 Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options – Antonio – Gland Surgery

  https://gs.amegroups.org/article/view/34807/html

  PPGLs have a high degree of heritability with 40% of cases carrying a germline mutation. […] The underlying mutation influences PPGL clinical presentation such as cell differentiation, specific catecholamine production, tumor location, malignant potential and genetic anticipation. […] The Cancer Genome Atlas divided PPGL into 3 clinically useful molecularly defined groups: Kinase signaling subtype, Pseudohypoxia subtype, and Wnt-altered subtype. […] Patients with these mutations typically present with pheochromocytoma having adrenergic biochemical phenotype corresponding to its high expression of phenylethanolamine N-methyltransferase (PNMT) that converts norepinephrine to epinephrine. […] SDHx mutations are associated with PPGLs as well as gastrointestinal stromal tumors, pituitary adenomas, chondromas, neuroblastomas and very rarely gastroenteropancreatic tumors.

• #12 Insights into Mechanisms of Pheochromocytomas and Paragangliomas Driven by Known or New Genetic Drivers

  https://www.mdpi.com/2072-6694/13/18/4602

  Pheochromocytomas and paragangliomas are rare tumors of neural crest origin. Their remarkable genetic diversity and high heritability have enabled discoveries of bona fide cancer driver genes with an impact on diagnosis and clinical management and have consistently shed light on new paradigms in cancer. […] In this review, we explore unique mechanisms of pheochromocytoma and paraganglioma initiation and management by drawing from recent examples involving rare mutations of hypoxia-related genes VHL, EPAS1 and SDHB, and of a poorly known susceptibility gene, TMEM127. These models expand our ability to predict variant pathogenicity, inform new functional domains, recognize environmental-gene connections, and highlight persistent therapeutic challenges for tumors with aggressive behavior. […] PPGLs have been classified into three clusters according to the molecular pathways involved in their pathogenesis. Cluster 1 consists of the pseudohypoxia pathway and includes tumors with either germline or somatic mutations in VHL, SDHA/B/C/D/AF2, EPAS1, EGLN1, EGLN2, FH, SLC25A11, and MDH2.

• #13 Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options – Antonio – Gland Surgery

  https://gs.amegroups.org/article/view/34807/html

  This subtype consists of adrenal pheochromocytomas associated with CSDE1 somatic mutations and MAML3 fusion genes activating the Wnt and Hedgehog signaling pathways. […] Identification of an underlying mutation whether germline or somatic, significantly influences current management and follow-up of PPGL. […] Some new mutations associated with PPGL identified were not included in the Cancer Genome Atlas: H3F3A, MDH2, PHD1, IRP1, SLC25A11 and DLST. […] H3F3A found in chromosome 1 encodes histone H3.3 protein responsible for nucleosome formation. […] A heterozygous variant on exon 4 of MDH2 was first detected in a patient with multiple metastatic paragangliomas. […] This gene was found to be responsible for encoding malate dehydrogenase enzyme that converts malate to oxaloacetate in the TCA cycle. […] The study demonstrated a lower MDH2 activity in mutated tumors but they were unable to document a subsequent accumulation of malate. […] The identification of this mutation can greatly affect the treatment and monitoring plan for patients harboring DLST mutations.

• #14 Epidemiology, clinical presentation, and diagnosis of paragangliomas – UpToDate

  https://www.uptodate.com/contents/epidemiology-clinical-presentation-and-diagnosis-of-paragangliomas

  Paragangliomas are rare neuroendocrine tumors that arise from the extra-adrenal autonomic paraganglia, small organs consisting mainly of neuroendocrine cells that are derived from the embryonic neural crest and have the ability to secrete catecholamines. […] Some hereditary paragangliomas, particularly those arising in the skull base and neck, have been linked to pathogenic variants in the genes encoding different subunits of the succinate dehydrogenase (SDH) enzyme complex. […] This topic review will cover the epidemiology, risk factors, molecular pathogenesis, histology, clinical manifestations, diagnosis, and genetic screening issues of paragangliomas arising at a variety of sites in the body.

• #15 Paraganglioma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549834/

  Paragangliomas are rare neuroendocrine tumors arising from extra-adrenal paraganglia. […] This activity explores paragangliomas, covering etiology, pathophysiology, evaluation, and management. […] Paragangliomas are tumors originating from the paraganglia. Researchers and clinicians refer to parasympathetic paragangliomas as nonchromaffin paragangliomas, contrasting them with chromaffin paragangliomas arising from chromaffin cells within the sympathetic paraganglia and the adrenal medulla. […] While usually sporadic, they may also present as part of familial syndromes. […] Most hereditary variants, especially involving the skull base and neck, are due to variations in the genes encoding different subunits of the SDH enzyme complex. […] The associated genetic variations are as follows: The SDH complex plays a central role in energy metabolism, functioning as an enzyme of the tricarboxylic acid cycle and as complex II of the mitochondrial respiratory chain.

• #16 Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement | Nature Reviews Endocrinology

  https://www.nature.com/articles/s41574-023-00926-0

  Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). […] PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. […] In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. […] As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells.

• #17 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations in: Endocrine-Related Cancer Volume 22 Issue 4 (2015)

  https://erc.bioscientifica.com/view/journals/erc/22/4/T71.xml

  Pathogenesis of PPGLs caused by SDH mutations remains poorly understood. SDH catalyzes the oxidation of succinate to fumarate in the Krebs cycle and functions as mitochondrial complex II by transferring the extracted electrons to ubiquinone in the electron transport chain. Loss of SDH activity leads to increased succinate and reactive oxygen species (ROS). Thus, succinate and ROS are considered as the signaling molecules that ultimately trigger tumor formation upon SDH mutations. Since discovery of the first mutations in familial PPGLs in 2000-2001, alternative models for tumor development have been advanced using different observations and experimental models that studied the consequences of SDH genetic loss. These models can be broadly classified as constitutive hypoxic drive, inhibition of developmental neuronal culling and histone/genome hypermethylation.

• #18 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma-paraganglioma syndromes characterized by germline SDHB and SDHD mutations | CRUK CC

  https://crukcambridgecentre.org.uk/papers/15-years-paraganglioma-genetics-and-mechanism-pheochromocytoma-paraganglioma-syndromes

  Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine neoplasms that derive from small paraganglionic tissues which are located from skull base to the pelvic floor. Genetic predisposition plays an important role in development of PPGLs. Since the discovery of first mutations in the succinate dehydrogenase D (SDHD) gene, which encodes the smallest subunit of mitochondrial complex II (SDH), genetic studies have revealed a major role for mutations in SDH subunit genes, primarily in SDHB and SDHD, in predisposition to both familial and non-familial PPGLs. […] SDH-mutated PPGLs show robust expression of hypoxia induced genes, and genomic and histone hypermethylation. These effects occur in part through succinate-mediated inhibition of alpha-ketoglutarate-dependent dioxygenases. However, details of mechanisms by which SDH mutations activate hypoxic pathways and trigger subsequent neoplastic transformation remain poorly understood. Here, we present a brief review of the genetic and mechanistic aspects of SDH-mutated PPGLs.

• #19 SciELO Brazil – The clinical genetics of phaeochromocytoma and paraganglioma The clinical genetics of phaeochromocytoma and paraganglioma

  https://www.scielo.br/j/aem/a/vmp3S83tXqvLVqJz64Zr3Mb/

  The common feature in all SDH mutations is the inactivation of the SDH complex which leads to the accumulation of succinate and increase in oxygen free radical production. Succinate affects HIF stability through its effects on post-translational regulation of HIF subunits, an essential step for the recognition of HIF for proteasome-mediated degradation. Therefore, accumulation of succinate and an increase in oxygen free radical production in SDH inactivation leads to stabilisation of HIF. […] Through similar mechanisms as in VHL, stabilisation of HIF- activate multiple hypoxia-dependent pathways leads to epigenetic modifications in HIF target genes (DNA and histone hypermethylation). These genes that are affected by hypermethylation have been implicated in many vital effects on cellular processes including apoptosis, angiogenesis, energy metabolism, proliferation, migration, and invasion of tumour cells. Thus, HIF- stabilisation in SDH mutations cause subsequent epigenetic modifications giving rise to multiple benign and malignant tumour pathology including phaeochromocytomas and paragangliomas.

• #20 SciELO Brazil – The clinical genetics of phaeochromocytoma and paraganglioma The clinical genetics of phaeochromocytoma and paraganglioma

  https://www.scielo.br/j/aem/a/vmp3S83tXqvLVqJz64Zr3Mb/

  The common feature in all SDH mutations is the inactivation of the SDH complex which leads to the accumulation of succinate and increase in oxygen free radical production. Succinate affects HIF stability through its effects on post-translational regulation of HIF subunits, an essential step for the recognition of HIF for proteasome-mediated degradation. Therefore, accumulation of succinate and an increase in oxygen free radical production in SDH inactivation leads to stabilisation of HIF. […] Through similar mechanisms as in VHL, stabilisation of HIF- activate multiple hypoxia-dependent pathways leads to epigenetic modifications in HIF target genes (DNA and histone hypermethylation). These genes that are affected by hypermethylation have been implicated in many vital effects on cellular processes including apoptosis, angiogenesis, energy metabolism, proliferation, migration, and invasion of tumour cells. Thus, HIF- stabilisation in SDH mutations cause subsequent epigenetic modifications giving rise to multiple benign and malignant tumour pathology including phaeochromocytomas and paragangliomas.

• #21 Diagnosis for Pheochromocytoma and Paraganglioma: A Joint Position Statement of the Korean Pheochromocytoma and Paraganglioma Task Force

  https://www.e-enm.org/journal/view.php?doi=10.3803/EnM.2020.908

  PPGLs associated with SDHB mutation have a high risk of metastases. […] Pathogenic germline variants in any of the SDHx subunit genes (SDHA/B/C/D) have been implicated in hereditary tumorigenesis of PPGLs. […] The majority of patients with hereditary PPGL syndromes (30% to 40%) have germline mutations in these SDHx subunit genes. […] Germline mutations of SDHB have been widely accepted as a high-risk factor for metastases, leading to metastatic PPGLs in 40% or more of affected patients. […] Therefore, loss of SDHB IHC staining in tumoral tissue suggests the presence of germline mutations in one of the SDHx genes with 100% sensitivity and 84% specificity.

• #22 Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options – Antonio – Gland Surgery

  https://gs.amegroups.org/article/view/34807/html

  SDHB mutation in particular was found to increase the risk for clinically aggressive PPGLs that are more likely to develop metastases or locally aggressive or recurrent tumors. […] Interestingly, when compared to SDHD variant carriers who have a standard mortality ratio (SMR) of 0.93 which is comparable to the general population, SDHB variant carriers have a greater SMR at 1.89 which increases to 2.88 among SDHB variant carriers with a personal history of PPGL. […] Given its risk for metastases and association with poor outcomes, multiple studies have been done to determine the PPGL penetrance among individuals with an underlying SDHB mutation. […] FH mutation predisposes an individual to a syndrome of leiomyomatosis, renal cell carcinoma together with pheochromocytoma or paraganglioma.

• #23 Multiple paragangliomas: a case report | BMC Medical Genomics | Full Text

  https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-020-00789-8

  Mutations in these genes predispose to different forms of paragangliomas (early, syndromic, multiple, and malignant). […] As multiple paragangliomas are rare, every case is important to study for a better understanding of genetics and molecular mechanisms causing their initiation and progression. […] We found a germline pathogenic variant in the SDHD gene in the patient. According to the literature, SDHD mutations are frequently associated with multiple paragangliomas. […] Results from all the studies indicate a high frequency of SDHx mutations in paragangliomas. Moreover, most multiple paragangliomas are associated with SDHx variants, predominantly SDHD mutations, which are in accordance with our results. […] We observed different spectra of somatic mutations in three tumors studied.

• #24 Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options – Antonio – Gland Surgery

  https://gs.amegroups.org/article/view/34807/html

  SDHB mutation in particular was found to increase the risk for clinically aggressive PPGLs that are more likely to develop metastases or locally aggressive or recurrent tumors. […] Interestingly, when compared to SDHD variant carriers who have a standard mortality ratio (SMR) of 0.93 which is comparable to the general population, SDHB variant carriers have a greater SMR at 1.89 which increases to 2.88 among SDHB variant carriers with a personal history of PPGL. […] Given its risk for metastases and association with poor outcomes, multiple studies have been done to determine the PPGL penetrance among individuals with an underlying SDHB mutation. […] FH mutation predisposes an individual to a syndrome of leiomyomatosis, renal cell carcinoma together with pheochromocytoma or paraganglioma.

• #25 Pheochromocytoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/124059-overview

  The succinate dehydrogenase complex subunit D protein is encoded by the SDHD gene, mutations in which cause pheochromocytomas, paragangliomas, and other tumors. In most tumors, inheritance of the mutation is autosomal dominant with biallelic expression of the SDHD gene. However, paternal imprinting appears to be the inheritance pattern in paragangliomas and, in particular, carotid body tumors resulting from the SDHD gene. […] The succinate dehydrogenase complex subunit B protein is encoded by the SDHB gene. Mutations in this gene are known to cause carotid body tumors and paragangliomas and are inherited in an autosomal dominant fashion. Paragangliomas caused by SDHB mutations have a higher rate of malignant transformation that those that are not. […] The succinate dehydrogenase subunit C protein is encoded by the SDHC gene, and mutations are known to cause paraganglioma. One family with a mutation in this gene showed maternal inheritance of the condition, but subsequent investigation has suggested an autosomal dominant inheritance pattern without evidence of imprinting.

• #26 Paraganglioma and pheochromocytoma upon maternal transmission of SDHDmutations | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-014-0111-8

  The SDHD gene encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme and tumor suppressor, succinate dehydrogenase. Mutations in this gene show a remarkable pattern of parent-of-origin related tumorigenesis, with almost all SDHD-related cases of head and neck paragangliomas and pheochromocytomas attributable to paternally-transmitted mutations. […] We found convincing genetic and immunohistochemical evidence for the maternally-related occurrence of a case of pheochromocytoma, and suggestive evidence in a case of jugular paraganglioma. […] Transmission of SDHD mutations via the maternal line can, in rare cases, result in tumorigenesis. Despite this finding, the overwhelming majority of carriers of maternally-transmitted mutations will remain tumor-free throughout life. […] Germline mutations of the SDHD gene show a 'parent-of-origin’ expression phenotype, with tumor development occurring only when mutations are inherited via the paternal line.

• #27 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations in: Endocrine-Related Cancer Volume 22 Issue 4 (2015)

  https://erc.bioscientifica.com/view/journals/erc/22/4/T71.xml

  The most common phenotypic manifestation of germline SDH mutations is the development of PPGL tumors. Gastrointestinal stromal tumors and renal carcinoma also develop in a small minority of subjects who carry germ line SDH mutations. HNPGL, especially the carotid body (CB) paraganglioma, are characteristically associated with germ line mutations in structural subunit genes SDHD, SDHC, SDHB, and in regulatory subunit genes SDHAF2. The CB is an acute oxygen-sensing organ that responds to hypoxia by increasing heart and ventilation rate. It has been recognized that the incidence of CB paragangliomas increase among high altitude dwellers and those with chronic cyanotic heart diseases. These observations suggested early on that the SDH mutations disrupt oxygen sensing of the CB by causing an inability to register presence of normal oxygen levels. The paraganglioma tumor formation may thus follow chronic hypoxic stimulation of the CB oxygen-sensing (chief) cells, either by environmental hypoxia or by SDH mutations that inhibit oxygen sensing.

• #28

  https://link.springer.com/article/10.1385/EP:17:2:97

  Pheochromocytomas and paragangliomas are rare tumors derived from chromaffin cells. […] Recent studies indicate that germ line mutations of genes encoding specific succinate dehydrogenase (SDH) subunits also predispose individuals to pheochromocytomas and paragangliomas. […] This review focuses on the genetics of these tumors and suggests a possible link between familial pheochromocytomas/paraganglioma genes and control of neuronal apoptosis during embryological development. […] Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer.

• #29 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma-paraganglioma syndromes characterized by germline SDHB and SDHD mutations | CRUK CC

  https://crukcambridgecentre.org.uk/papers/15-years-paraganglioma-genetics-and-mechanism-pheochromocytoma-paraganglioma-syndromes

  Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine neoplasms that derive from small paraganglionic tissues which are located from skull base to the pelvic floor. Genetic predisposition plays an important role in development of PPGLs. Since the discovery of first mutations in the succinate dehydrogenase D (SDHD) gene, which encodes the smallest subunit of mitochondrial complex II (SDH), genetic studies have revealed a major role for mutations in SDH subunit genes, primarily in SDHB and SDHD, in predisposition to both familial and non-familial PPGLs. […] SDH-mutated PPGLs show robust expression of hypoxia induced genes, and genomic and histone hypermethylation. These effects occur in part through succinate-mediated inhibition of alpha-ketoglutarate-dependent dioxygenases. However, details of mechanisms by which SDH mutations activate hypoxic pathways and trigger subsequent neoplastic transformation remain poorly understood. Here, we present a brief review of the genetic and mechanistic aspects of SDH-mutated PPGLs.

• #30 SciELO Brazil – The clinical genetics of phaeochromocytoma and paraganglioma The clinical genetics of phaeochromocytoma and paraganglioma

  https://www.scielo.br/j/aem/a/vmp3S83tXqvLVqJz64Zr3Mb/

  The common feature in all SDH mutations is the inactivation of the SDH complex which leads to the accumulation of succinate and increase in oxygen free radical production. Succinate affects HIF stability through its effects on post-translational regulation of HIF subunits, an essential step for the recognition of HIF for proteasome-mediated degradation. Therefore, accumulation of succinate and an increase in oxygen free radical production in SDH inactivation leads to stabilisation of HIF. […] Through similar mechanisms as in VHL, stabilisation of HIF- activate multiple hypoxia-dependent pathways leads to epigenetic modifications in HIF target genes (DNA and histone hypermethylation). These genes that are affected by hypermethylation have been implicated in many vital effects on cellular processes including apoptosis, angiogenesis, energy metabolism, proliferation, migration, and invasion of tumour cells. Thus, HIF- stabilisation in SDH mutations cause subsequent epigenetic modifications giving rise to multiple benign and malignant tumour pathology including phaeochromocytomas and paragangliomas.

• #31 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations in: Endocrine-Related Cancer Volume 22 Issue 4 (2015)

  https://erc.bioscientifica.com/view/journals/erc/22/4/T71.xml

  Recent genome-wide expression profiling studies show strong induction of hypoxia and angiogenesis pathways in SDH- and VHL-related PPGL. SDH and VHL mutations induce both protein encoding mRNAs and miRNAs (miR-210) that are implicated in cellular adaptation to hypoxia. Although certain differences in the induced genes were observed, the broad overlap amongst the hypoxia induced genes between SDH- and VHL-related paragangliomas strongly suggest that pathogenesis of SDH tumors involves constitutive hypoxic stimulation. […] Broad transcriptional overlap between SDH and VHL-related PPGL, and constitutive activation of the HIFs in VHL suggested that HIFs may also mediate tumor formation in SDH-mutated paragangliomas. HIF1 and/or HIF2 were detected by immunohistochemistry in both SDH-mutated and sporadic HNPGL. In vitro studies using cell lines showed that siRNA-mediated knockdown of SDH subunits led to stabilization of HIF1. These studies linked increased succinate or ROS levels to the stabilization of HIFs.

• #32 SciELO Brazil – The clinical genetics of phaeochromocytoma and paraganglioma The clinical genetics of phaeochromocytoma and paraganglioma

  https://www.scielo.br/j/aem/a/vmp3S83tXqvLVqJz64Zr3Mb/

  The common feature in all SDH mutations is the inactivation of the SDH complex which leads to the accumulation of succinate and increase in oxygen free radical production. Succinate affects HIF stability through its effects on post-translational regulation of HIF subunits, an essential step for the recognition of HIF for proteasome-mediated degradation. Therefore, accumulation of succinate and an increase in oxygen free radical production in SDH inactivation leads to stabilisation of HIF. […] Through similar mechanisms as in VHL, stabilisation of HIF- activate multiple hypoxia-dependent pathways leads to epigenetic modifications in HIF target genes (DNA and histone hypermethylation). These genes that are affected by hypermethylation have been implicated in many vital effects on cellular processes including apoptosis, angiogenesis, energy metabolism, proliferation, migration, and invasion of tumour cells. Thus, HIF- stabilisation in SDH mutations cause subsequent epigenetic modifications giving rise to multiple benign and malignant tumour pathology including phaeochromocytomas and paragangliomas.

• #33 SciELO Brazil – The clinical genetics of phaeochromocytoma and paraganglioma The clinical genetics of phaeochromocytoma and paraganglioma

  https://www.scielo.br/j/aem/a/vmp3S83tXqvLVqJz64Zr3Mb/

  The second cluster of genes cause catecholamine secreting tumours by way of affecting the kinase signalling pathways. Activation of RET proto-oncogene in MEN 2 and inactivation of NF1 leads to activation of RAS/MAPK and PI3/AKT signalling pathways. Similarly, TMEM127 mutation activates the mTOR pathway while MAX mutation too has been established to affect the downstream mTOR pathway via the MYC-MAX- MXD1 network. […] However, the pathogenesis of phaeochromocytoma may not be quite as simple, where there can be significant overlap due to high degree of redundancy and cross-talk between constituents of these pathways. For example, mTOR can activate HIF, while MYC cooperates with HIF2 in oncogenesis. Furthermore, there is increasing evidence that SDH and related mutations can lead to the build-up of succinate which can act as an oncometabolite causing marked changing in patterns of gene methylation.

• #34 SciELO Brazil – The clinical genetics of phaeochromocytoma and paraganglioma The clinical genetics of phaeochromocytoma and paraganglioma

  https://www.scielo.br/j/aem/a/vmp3S83tXqvLVqJz64Zr3Mb/

  The second cluster of genes cause catecholamine secreting tumours by way of affecting the kinase signalling pathways. Activation of RET proto-oncogene in MEN 2 and inactivation of NF1 leads to activation of RAS/MAPK and PI3/AKT signalling pathways. Similarly, TMEM127 mutation activates the mTOR pathway while MAX mutation too has been established to affect the downstream mTOR pathway via the MYC-MAX- MXD1 network. […] However, the pathogenesis of phaeochromocytoma may not be quite as simple, where there can be significant overlap due to high degree of redundancy and cross-talk between constituents of these pathways. For example, mTOR can activate HIF, while MYC cooperates with HIF2 in oncogenesis. Furthermore, there is increasing evidence that SDH and related mutations can lead to the build-up of succinate which can act as an oncometabolite causing marked changing in patterns of gene methylation.

• #35 Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options – Antonio – Gland Surgery

  https://gs.amegroups.org/article/view/34807/html

  This subtype consists of adrenal pheochromocytomas associated with CSDE1 somatic mutations and MAML3 fusion genes activating the Wnt and Hedgehog signaling pathways. […] Identification of an underlying mutation whether germline or somatic, significantly influences current management and follow-up of PPGL. […] Some new mutations associated with PPGL identified were not included in the Cancer Genome Atlas: H3F3A, MDH2, PHD1, IRP1, SLC25A11 and DLST. […] H3F3A found in chromosome 1 encodes histone H3.3 protein responsible for nucleosome formation. […] A heterozygous variant on exon 4 of MDH2 was first detected in a patient with multiple metastatic paragangliomas. […] This gene was found to be responsible for encoding malate dehydrogenase enzyme that converts malate to oxaloacetate in the TCA cycle. […] The study demonstrated a lower MDH2 activity in mutated tumors but they were unable to document a subsequent accumulation of malate. […] The identification of this mutation can greatly affect the treatment and monitoring plan for patients harboring DLST mutations.

• #36 Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options – Antonio – Gland Surgery

  https://gs.amegroups.org/article/view/34807/html

  This subtype consists of adrenal pheochromocytomas associated with CSDE1 somatic mutations and MAML3 fusion genes activating the Wnt and Hedgehog signaling pathways. […] Identification of an underlying mutation whether germline or somatic, significantly influences current management and follow-up of PPGL. […] Some new mutations associated with PPGL identified were not included in the Cancer Genome Atlas: H3F3A, MDH2, PHD1, IRP1, SLC25A11 and DLST. […] H3F3A found in chromosome 1 encodes histone H3.3 protein responsible for nucleosome formation. […] A heterozygous variant on exon 4 of MDH2 was first detected in a patient with multiple metastatic paragangliomas. […] This gene was found to be responsible for encoding malate dehydrogenase enzyme that converts malate to oxaloacetate in the TCA cycle. […] The study demonstrated a lower MDH2 activity in mutated tumors but they were unable to document a subsequent accumulation of malate. […] The identification of this mutation can greatly affect the treatment and monitoring plan for patients harboring DLST mutations.

• #37 Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options – Antonio – Gland Surgery

  https://gs.amegroups.org/article/view/34807/html

  This subtype consists of adrenal pheochromocytomas associated with CSDE1 somatic mutations and MAML3 fusion genes activating the Wnt and Hedgehog signaling pathways. […] Identification of an underlying mutation whether germline or somatic, significantly influences current management and follow-up of PPGL. […] Some new mutations associated with PPGL identified were not included in the Cancer Genome Atlas: H3F3A, MDH2, PHD1, IRP1, SLC25A11 and DLST. […] H3F3A found in chromosome 1 encodes histone H3.3 protein responsible for nucleosome formation. […] A heterozygous variant on exon 4 of MDH2 was first detected in a patient with multiple metastatic paragangliomas. […] This gene was found to be responsible for encoding malate dehydrogenase enzyme that converts malate to oxaloacetate in the TCA cycle. […] The study demonstrated a lower MDH2 activity in mutated tumors but they were unable to document a subsequent accumulation of malate. […] The identification of this mutation can greatly affect the treatment and monitoring plan for patients harboring DLST mutations.

• #38 Clinical Syndromes and Genetic Screening Strategies of Pheochromocytoma and Paraganglioma

  https://www.jkcvhl.com/~jkcvhlco/index.php/jkcvhl/article/download/113/226/1378

  Pheochromocytomas (PCCs) and paragangliomas (PGLs) are thought to have the highest degree of heritability among human tumors, and it has been estimated that 60% of the patients have genetic abnormalities. […] Up to 40% of PCC and PGL are attributed to germline mutations, and overall, germline and somatic mutations can be present in 60% of PCC and PGL. […] To date, there are 29 genes known to be related to PCC and PGL and the exploration of new genes is far from over. […] Mutations in the succinate dehydrogenase (SDH, mitochondrial complex II) and its subunit genes (SDHA, SDHB, SDHC, SDHD, and SDHAF2) can lead to FPGLs. […] It is worth noting that mutation in SDHB is possibly related to malignancy and poor prognosis. […] The VHL gene encodes the VHL protein (pVHL), which has a wide range of functions, the most important being the degradation of hypoxia inducible factors (HIFs). Without degradation, HIFs can be translocated to the nucleus and initiate transcription of multiple target genes, which can promote cell proliferation, angiogenesis, erythropoiesis, and anaerobe metabolism.

• #39 New insights on the pathogenesis of paraganglioma… | F1000Research

  https://f1000research.com/articles/7-1500

  Recent advances in our understanding of the pathogenesis of PPGL had significantly changed our approach to the condition. The change in classification moved different forms of PPGLs into pathogenesis-driven groups, which allowed a better understanding of major disease-related features: clinical presentation, biochemical approach, and predisposition to malignant course and possible differences in therapy and follow-up. […] Understanding differential pathogenetic pathways in different forms of PPGL allowed a better design of biochemical tests with a recent use of metabolomics through high-end nuclear magnetic resonance spectroscopy as a differential tool on a biochemical level. […] Pathogenesis-based knowledge had also allowed us to design new therapeutic approaches; the best example would be the use of specific HIF-2 antagonists (PT2399) and prolyl hydroxylase activators (R59949 and KRH102053) that promote HIF hydroxylation, thus restoring VHL-driven recognition and rapid degradation.

• #40 Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement | Nature Reviews Endocrinology

  https://www.nature.com/articles/s41574-023-00926-0

  In patients with SDHB PPGLs, the rate of progression (whether local or represented by metastasis) is often dependent on the initial tumour size (the rate is higher in tumours 5cm), location (higher in extra-adrenal tumours), plasma levels of 3-methoxytyramine (higher at elevated 3-methoxtytyramine levels) and high proliferation indices, including Ki-67 and mitotic count. […] In patients with SDHB PPGLs, the goals of surgery are complete tumour resection and avoidance of capsular disruption to minimize the risk of local recurrence and dissemination of tumour cells. […] Patients with SDHB phaeochromocytomas should undergo total adrenalectomy rather than a cortical-sparing procedure, regardless of tumour size. […] The risk of leaving potentially malignant cells in situ is high if a cortical-sparing technique is performed. […] The 2017 World Health Organization classification described all PPGL as potentially metastatic, noting that the SDHB subtype is at an even higher risk than other hereditary forms.

• #41 Paraganglioma | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/26614

  Histologically, paragangliomas and pheochromocytomas are nearly identical, differing primarily in the presence of chromaffin cells. On a cellular level, sympathetic and parasympathetic paraganglioma are indistinguishable. […] Approximately 20% of extra-adrenal paragangliomas are malignant, while 10% of pheochromocytomas are malignant. Nearly all paragangliomas in the head and neck are benign. Unfortunately, no combination of clinical, histopathologic, or biochemical features can reliably predict biologic behavior. Tumor deposits in tissues that do not normally contain chromaffin cells are the only confirmation of malignancy.

• #42 Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement | Nature Reviews Endocrinology

  https://www.nature.com/articles/s41574-023-00926-0

  However, the recurrence rate of SDHB PPGLs is high. […] These tumours are also at high risk of aggressive behaviour, with at least 30% of patients developing metastatic disease and a predisposition to developing other tumours, such as gastrointestinal stromal tumours, renal cell carcinoma and pituitary tumours. […] The majority of SDHB phaeochromocytomas and sympathetic paragangliomas are associated with increased levels of normetanephrine or 3-methoxytyramine as measured by liquid chromatography with tandem mass spectrometry, with plasma analyses being more accurate than urine-based measurements. […] The advent of SSTR-targeted PET (performed either as PETCT or PETMRI) has superseded other PET radiopharmaceuticals or SSTR scintigraphy for the detection of PPGLs in patients with SDHB pathogenic variants.

• #43 Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement | Nature Reviews Endocrinology

  https://www.nature.com/articles/s41574-023-00926-0

  Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). […] PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. […] In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. […] As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells.

• #44 Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement | Nature Reviews Endocrinology

  https://www.nature.com/articles/s41574-023-00926-0

  In patients with SDHB PPGLs, the rate of progression (whether local or represented by metastasis) is often dependent on the initial tumour size (the rate is higher in tumours 5cm), location (higher in extra-adrenal tumours), plasma levels of 3-methoxytyramine (higher at elevated 3-methoxtytyramine levels) and high proliferation indices, including Ki-67 and mitotic count. […] In patients with SDHB PPGLs, the goals of surgery are complete tumour resection and avoidance of capsular disruption to minimize the risk of local recurrence and dissemination of tumour cells. […] Patients with SDHB phaeochromocytomas should undergo total adrenalectomy rather than a cortical-sparing procedure, regardless of tumour size. […] The risk of leaving potentially malignant cells in situ is high if a cortical-sparing technique is performed. […] The 2017 World Health Organization classification described all PPGL as potentially metastatic, noting that the SDHB subtype is at an even higher risk than other hereditary forms.

• #45 New insights on the pathogenesis of paraganglioma… | F1000Research

  https://f1000research.com/articles/7-1500

  Recent advances in our understanding of the pathogenesis of PPGL had significantly changed our approach to the condition. The change in classification moved different forms of PPGLs into pathogenesis-driven groups, which allowed a better understanding of major disease-related features: clinical presentation, biochemical approach, and predisposition to malignant course and possible differences in therapy and follow-up. […] Understanding differential pathogenetic pathways in different forms of PPGL allowed a better design of biochemical tests with a recent use of metabolomics through high-end nuclear magnetic resonance spectroscopy as a differential tool on a biochemical level. […] Pathogenesis-based knowledge had also allowed us to design new therapeutic approaches; the best example would be the use of specific HIF-2 antagonists (PT2399) and prolyl hydroxylase activators (R59949 and KRH102053) that promote HIF hydroxylation, thus restoring VHL-driven recognition and rapid degradation.

• #46 Insights into Mechanisms of Pheochromocytomas and Paragangliomas Driven by Known or New Genetic Drivers

  https://www.mdpi.com/2072-6694/13/18/4602

  In cases where surgery is not feasible, tumor burden, disease progression, or symptomatic status should guide treatment options that include local therapies (radiotherapy, radiofrequency ablation, embolization, among others), radionucleotide therapy and chemotherapy. […] Another potential and even more promising therapy targeting molecular disruption of PPGLs involve HIF inhibitors, in particular HIF-2α, which has been identified as one of the main oncogenic drivers in PPGL development and is overexpressed in VHL, SDH, and EPAS1-mutant PPGLs. […] The remarkable association between CCHD and EPAS1 mutated-PPGLs should spur studies to further investigate and model the impact of environmental influences in PPGL tumorigenesis that may also illuminate our knowledge of other cancers.

• #47 Insights into Mechanisms of Pheochromocytomas and Paragangliomas Driven by Known or New Genetic Drivers

  https://www.mdpi.com/2072-6694/13/18/4602

  This classification underlies the diverse mechanisms and signals that can initiate PPGLs, although it remains challenging to predict the disease course. […] Although the biological behavior of PPGLs cannot be anticipated, specific genotypes have been associated with an increased risk of metastasis. For example, SDHB mutations confer a higher risk of metastatic progression. Similarly, somatic MAML3 fusions, often accompanied by disruption of TERT and/or ATRX mutations are enriched in aggressive and/or metastatic tumors. […] The first line of treatment for all PPGLs should be tumor resection with pre-operative management of catecholamine-related symptoms that are usually achieved by alpha-blockade, regardless of mutation status. […] However, knowledge of the genotype impacts on surgical planning, as patients diagnosed with, or at risk of, bilateral pheochromocytomas are recommended to undergo cortical-sparing surgery.

• #48 Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement | Nature Reviews Endocrinology

  https://www.nature.com/articles/s41574-023-00926-0

  In patients with SDHB PPGLs, the rate of progression (whether local or represented by metastasis) is often dependent on the initial tumour size (the rate is higher in tumours 5cm), location (higher in extra-adrenal tumours), plasma levels of 3-methoxytyramine (higher at elevated 3-methoxtytyramine levels) and high proliferation indices, including Ki-67 and mitotic count. […] In patients with SDHB PPGLs, the goals of surgery are complete tumour resection and avoidance of capsular disruption to minimize the risk of local recurrence and dissemination of tumour cells. […] Patients with SDHB phaeochromocytomas should undergo total adrenalectomy rather than a cortical-sparing procedure, regardless of tumour size. […] The risk of leaving potentially malignant cells in situ is high if a cortical-sparing technique is performed. […] The 2017 World Health Organization classification described all PPGL as potentially metastatic, noting that the SDHB subtype is at an even higher risk than other hereditary forms.

• #49 Insights into Mechanisms of Pheochromocytomas and Paragangliomas Driven by Known or New Genetic Drivers

  https://www.mdpi.com/2072-6694/13/18/4602

  In cases where surgery is not feasible, tumor burden, disease progression, or symptomatic status should guide treatment options that include local therapies (radiotherapy, radiofrequency ablation, embolization, among others), radionucleotide therapy and chemotherapy. […] Another potential and even more promising therapy targeting molecular disruption of PPGLs involve HIF inhibitors, in particular HIF-2α, which has been identified as one of the main oncogenic drivers in PPGL development and is overexpressed in VHL, SDH, and EPAS1-mutant PPGLs. […] The remarkable association between CCHD and EPAS1 mutated-PPGLs should spur studies to further investigate and model the impact of environmental influences in PPGL tumorigenesis that may also illuminate our knowledge of other cancers.

• #50 SciELO Brazil – The clinical genetics of phaeochromocytoma and paraganglioma The clinical genetics of phaeochromocytoma and paraganglioma

  https://www.scielo.br/j/aem/a/vmp3S83tXqvLVqJz64Zr3Mb/

  The pathogenesis of the hereditary nature of phaeochromocytoma can be described in two main clusters. The first cluster contains pseudohypoxia-driven tumours including VHL, SDH, EGLN1 and HIF2A mutant tumours. The second cluster contained the kinase signalling subgroup including the RET, NF1, TMEM 127 and MAX mutant tumours. […] The feature common to all cluster 1 tumours is the activation of HIFs. Hypoxia inducible factors (HIFs) are transcription factors induced as a physiological response to cellular hypoxia. In the presence of VHL, SDH, EGLN1 and HIF2A mutations, HIFs are induced and stabilised, pointing the cell towards a pseudo-hypoxic state. Pseudohypoxia occurs when HIF pathways are constitutively activated, regardless of oxygen levels. This cellular pseudohypoxia leads to epigenetic modifications in HIF target genes affecting multiple cellular processes including apoptosis, angiogenesis, proliferation, migration, and invasion.

• #51 SciELO Brazil – The clinical genetics of phaeochromocytoma and paraganglioma The clinical genetics of phaeochromocytoma and paraganglioma

  https://www.scielo.br/j/aem/a/vmp3S83tXqvLVqJz64Zr3Mb/

  The common feature in all SDH mutations is the inactivation of the SDH complex which leads to the accumulation of succinate and increase in oxygen free radical production. Succinate affects HIF stability through its effects on post-translational regulation of HIF subunits, an essential step for the recognition of HIF for proteasome-mediated degradation. Therefore, accumulation of succinate and an increase in oxygen free radical production in SDH inactivation leads to stabilisation of HIF. […] Through similar mechanisms as in VHL, stabilisation of HIF- activate multiple hypoxia-dependent pathways leads to epigenetic modifications in HIF target genes (DNA and histone hypermethylation). These genes that are affected by hypermethylation have been implicated in many vital effects on cellular processes including apoptosis, angiogenesis, energy metabolism, proliferation, migration, and invasion of tumour cells. Thus, HIF- stabilisation in SDH mutations cause subsequent epigenetic modifications giving rise to multiple benign and malignant tumour pathology including phaeochromocytomas and paragangliomas.

• #52 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma-paraganglioma syndromes characterized by germline SDHB and SDHD mutations | CRUK CC

  https://crukcambridgecentre.org.uk/papers/15-years-paraganglioma-genetics-and-mechanism-pheochromocytoma-paraganglioma-syndromes

  Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine neoplasms that derive from small paraganglionic tissues which are located from skull base to the pelvic floor. Genetic predisposition plays an important role in development of PPGLs. Since the discovery of first mutations in the succinate dehydrogenase D (SDHD) gene, which encodes the smallest subunit of mitochondrial complex II (SDH), genetic studies have revealed a major role for mutations in SDH subunit genes, primarily in SDHB and SDHD, in predisposition to both familial and non-familial PPGLs. […] SDH-mutated PPGLs show robust expression of hypoxia induced genes, and genomic and histone hypermethylation. These effects occur in part through succinate-mediated inhibition of alpha-ketoglutarate-dependent dioxygenases. However, details of mechanisms by which SDH mutations activate hypoxic pathways and trigger subsequent neoplastic transformation remain poorly understood. Here, we present a brief review of the genetic and mechanistic aspects of SDH-mutated PPGLs.

• #53 SciELO Brazil – The clinical genetics of phaeochromocytoma and paraganglioma The clinical genetics of phaeochromocytoma and paraganglioma

  https://www.scielo.br/j/aem/a/vmp3S83tXqvLVqJz64Zr3Mb/

  The second cluster of genes cause catecholamine secreting tumours by way of affecting the kinase signalling pathways. Activation of RET proto-oncogene in MEN 2 and inactivation of NF1 leads to activation of RAS/MAPK and PI3/AKT signalling pathways. Similarly, TMEM127 mutation activates the mTOR pathway while MAX mutation too has been established to affect the downstream mTOR pathway via the MYC-MAX- MXD1 network. […] However, the pathogenesis of phaeochromocytoma may not be quite as simple, where there can be significant overlap due to high degree of redundancy and cross-talk between constituents of these pathways. For example, mTOR can activate HIF, while MYC cooperates with HIF2 in oncogenesis. Furthermore, there is increasing evidence that SDH and related mutations can lead to the build-up of succinate which can act as an oncometabolite causing marked changing in patterns of gene methylation.

• #54

  https://link.springer.com/article/10.1385/EP:17:2:97

  Pheochromocytomas and paragangliomas are rare tumors derived from chromaffin cells. […] Recent studies indicate that germ line mutations of genes encoding specific succinate dehydrogenase (SDH) subunits also predispose individuals to pheochromocytomas and paragangliomas. […] This review focuses on the genetics of these tumors and suggests a possible link between familial pheochromocytomas/paraganglioma genes and control of neuronal apoptosis during embryological development. […] Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer.

• #55 Insights into Mechanisms of Pheochromocytomas and Paragangliomas Driven by Known or New Genetic Drivers

  https://www.mdpi.com/2072-6694/13/18/4602

  Pheochromocytomas and paragangliomas are rare tumors of neural crest origin. Their remarkable genetic diversity and high heritability have enabled discoveries of bona fide cancer driver genes with an impact on diagnosis and clinical management and have consistently shed light on new paradigms in cancer. […] In this review, we explore unique mechanisms of pheochromocytoma and paraganglioma initiation and management by drawing from recent examples involving rare mutations of hypoxia-related genes VHL, EPAS1 and SDHB, and of a poorly known susceptibility gene, TMEM127. These models expand our ability to predict variant pathogenicity, inform new functional domains, recognize environmental-gene connections, and highlight persistent therapeutic challenges for tumors with aggressive behavior. […] PPGLs have been classified into three clusters according to the molecular pathways involved in their pathogenesis. Cluster 1 consists of the pseudohypoxia pathway and includes tumors with either germline or somatic mutations in VHL, SDHA/B/C/D/AF2, EPAS1, EGLN1, EGLN2, FH, SLC25A11, and MDH2.

• #56 Frontiers | Editorial: Recent Advances in Pheochromocytoma and Paraganglioma: Molecular Pathogenesis, Clinical Impacts, and Therapeutic Perspective

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.720983/full

  In this Research Topic, we have collected recent developments in research into Pheochromocytomas and Paragangliomas (PPGLs), highlighting their molecular mechanisms, clinical manifestations, and improved therapeutic management. […] Recent advances in understanding of the molecular biology of PPGLs, however, offer potential to open pathways to improve therapeutic interventions for PPGL tumors. […] Pseudohypoxia plays important roles in the tumourigenesis of PPGLs. Mutations in Von Hippel-Lindau (VHL) and hypoxia-induced factor (HIF) related genes, including PHD, VHL, HIF-2A (EPAS1), and SDHx, which are known as VHL/HIF axis genes, are common in PPGLs. […] VHL/HIF-mediated pseudohypoxia has a critical role in the pathogenesis of PPGLs. […] Succinate plays critical roles in PPGL pathogenesis and the accumulation of succinate receptor 1 (SUCNR1) in SDHx mutated PPGLs has been previously reported. […] the information presented in this Research Topic provides an underlying molecular and genetic spectrum of PPGLs, unveiling their clinical implications, thereby enriching our understanding of the pathogenesis of the disease, which could improve clinical outcomes in patients with PPGLs.

Zobacz więcej