Pheochromocytoma and Paraganglioma

Overview

Literature Analysis

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Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (25)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
SDHB 1p36.1-p35 IP, SDH, CWS2, PGL4, SDH1, SDH2, SDHIP -SDHB and Pheochromocytoma and Paraganglioma
351
RET 10q11.2 PTC, MTC1, HSCR1, MEN2A, MEN2B, RET51, CDHF12, CDHR16, RET-ELE1 -RET and Pheochromocytoma and Paraganglioma
349
SDHD 11q23 PGL, CBT1, CWS3, PGL1, QPs3, SDH4, cybS, CII-4 -SDHD and Pheochromocytoma and Paraganglioma
325
SDHC 1q23.3 CYBL, PGL3, QPS1, SDH3, CYB560 -SDHC and Pheochromocytoma and Paraganglioma
188
VHL 3p25.3 RCA1, VHL1, pVHL, HRCA1 -VHL and Pheochromocytoma and Paraganglioma
133
NF1 17q11.2 WSS, NFNS, VRNF -NF1 and Pheochromocytoma and Paraganglioma
96
PGLS 19p13.2 6PGL -PGLS and Pheochromocytoma and Paraganglioma
89
SDHA 5p15 FP, PGL5, SDH1, SDH2, SDHF, CMD1GG -SDHA and Pheochromocytoma and Paraganglioma
58
TMEM127 2q11.2 -TMEM127 and Pheochromocytoma and Paraganglioma
50
SDHAF2 11q12.2 PGL2, SDH5, C11orf79 -SDHAF2 and Pheochromocytoma and Paraganglioma
48
HIF1A 14q23.2 HIF1, MOP1, PASD8, HIF-1A, bHLHe78, HIF-1alpha, HIF1-ALPHA -HIF1A and Pheochromocytoma
17
EPAS1 2p21-p16 HLF, MOP2, ECYT4, HIF2A, PASD2, bHLHe73 -EPAS1 and Pheochromocytoma and Paraganglioma
10
EGLN1 1q42.1 HPH2, PHD2, SM20, ECYT3, HALAH, HPH-2, HIFPH2, ZMYND6, C1orf12, HIF-PH2 -EGLN1 and Pheochromocytoma
7
EGLN3 14q13.1 PHD3, HIFPH3, HIFP4H3 -EGLN3 and Pheochromocytoma
7
GDNF 5p13.1-p12 ATF1, ATF2, HSCR3, HFB1-GDNF -GDNF and Pheochromocytoma
7
MAX 14q23 bHLHd4 Germline
-MAX and Pheochromocytoma
6
RBP3 10q11.2 IRBP, RBPI, RP66, D10S64, D10S65, D10S66 -RBP3 and Pheochromocytoma
5
KIF1B 1p36.2 KLP, CMT2, CMT2A, CMT2A1, HMSNII, NBLST1 -KIF1B and Pheochromocytoma
5
CD3D 11q23 T3D, IMD19, CD3-DELTA -CD3D and Pheochromocytoma and Paraganglioma
4
KCNJ5 11q24 CIR, GIRK4, KATP1, LQT13, KIR3.4 -KCNJ5 and Pheochromocytoma
3
CHGA 14q32 CGA -CHGA and Pheochromocytoma
2
NCAM1 11q23.1 CD56, NCAM, MSK39 -NCAM1 and Pheochromocytoma and Paraganglioma
2
LGALS3 14q22.3 L31, GAL3, MAC2, CBP35, GALBP, GALIG, LGALS2 -LGALS3 and Pheochromocytoma
1
MCM2 3q21 BM28, CCNL1, CDCL1, cdc19, D3S3194, MITOTIN -MCM2 and Pheochromocytoma
1
MIB1 18q11.2 MIB, DIP1, ZZZ6, DIP-1, LVNC7, ZZANK2 -MIB1 and Pheochromocytoma
1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Oudijk L, Neuhofer CM, Lichtenauer UD, et al.
Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations.
Eur J Endocrinol. 2015; 173(1):43-52 [PubMed] Related Publications
OBJECTIVE: Pheochromocytomas (PCCs) are neuroendocrine tumors that occur in the adrenal medulla, whereas paragangliomas (PGLs) arise from paraganglia in the head, neck, thorax, or abdomen. In a variety of tumors, cancer cells with stem cell-like properties seem to form the basis of tumor initiation because of their ability to self-renew and proliferate. Specifically targeting this small cell population may lay the foundation for more effective therapeutic approaches. In the present study, we intended to identify stem cells in PCCs/PGLs.
DESIGN: We examined the immunohistochemical expression of 11 stem cell markers (SOX2, LIN28, NGFR, THY1, PREF1, SOX17, NESTIN, CD117, OCT3/4, NANOG, and CD133) on tissue microarrays containing 208 PCCs/PGLs with different genetic backgrounds from five European centers.
RESULTS: SOX2, LIN28, NGFR, and THY1 were expressed in more than 10% of tumors, and PREF1, SOX17, NESTIN, and CD117 were expressed in <10% of the samples. OCT3/4, NANOG, and CD133 were not detectable at all. Double staining for chromogranin A/SOX2 and S100/SOX2 demonstrated SOX2 immunopositivity in both tumor and adjacent sustentacular cells. The expression of SOX2, SOX17, NGFR, LIN28, PREF1, and THY1 was significantly associated with mutations in one of the succinate dehydrogenase (SDH) genes. In addition, NGFR expression was significantly correlated with metastatic disease.
CONCLUSION: Immunohistochemical expression of stem cell markers was found in a subset of PCCs/PGLs. Further studies are required to validate whether some stem cell-associated markers, such as SOX2, could serve as targets for therapeutic approaches and whether NGFR expression could be utilized as a predictor of malignancy.

Padmanabhan S, Caulfield M, Dominiczak AF
Genetic and molecular aspects of hypertension.
Circ Res. 2015; 116(6):937-59 [PubMed] Related Publications
Until recently, significant advances in our understanding of the mechanisms of blood pressure regulation arose from studies of monogenic forms of hypertension and hypotension, which identified rare variants that primarily alter renal salt handling. Genome-wide association and exome sequencing studies over the past 6 years have resulted in an unparalleled burst of discovery in the genetics of blood pressure regulation and hypertension. More importantly, genome-wide association studies, while expanding the list of common genetic variants associated with blood pressure and hypertension, are also uncovering novel pathways of blood pressure regulation that augur a new era of novel drug development, repurposing, and stratification in the management of hypertension. In this review, we describe the current state of the art of the genetic and molecular basis of blood pressure and hypertension.

Cascón A, Comino-Méndez I, Currás-Freixes M, et al.
Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene.
J Natl Cancer Inst. 2015; 107(5) [PubMed] Related Publications
Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which encodes a Krebs cycle enzyme. Whole-exome sequencing was applied to tumor DNA obtained from a man age 55 years diagnosed with multiple malignant paragangliomas. Data were analyzed with the two-sided Student's t and Mann-Whitney U tests with Bonferroni correction for multiple comparisons. Between six- and 14-fold lower levels of MDH2 expression were observed in MDH2-mutated tumors compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate (mean ± SD: wild-type [WT] = 1±0.18; KD = 2.24±0.17, P = .043) and fumarate (WT = 1±0.06; KD = 2.6±0.25, P = .033), which was reversed by transient introduction of WT MDH2 cDNA. Segregation of the mutation with disease and absence of MDH2 in mutated tumors revealed MDH2 as a novel pheochromocytoma/paraganglioma susceptibility gene.

Cassol C, Mete O
Endocrine manifestations of von Hippel-Lindau disease.
Arch Pathol Lab Med. 2015; 139(2):263-8 [PubMed] Related Publications
von Hippel-Lindau (VHL) disease is an autosomal dominant disorder caused by heterozygous mutations in the VHL tumor suppressor gene that is characterized by the occurrence of multiple endocrine and nonendocrine lesions. This review focuses on the endocrine manifestations of VHL disease. Pancreatic neuroendocrine proliferations (ductuloinsular complexes, islet dysplasia, endocrine microadenoma, and neuroendocrine tumors), pheochromocytomas, and extra-adrenal paragangliomas are important endocrine manifestations of VHL disease. They frequently display characteristic clinical, biochemical, and histopathologic features that, although not pathognomonic, can be helpful in suggesting VHL disease as the underlying etiology and distinguishing these tumors from sporadic cases. Recent improvements in treatment and outcomes of renal cell carcinomas have allowed pancreatic neuroendocrine tumors to emerge as a significant source of metastatic disease, making the accurate recognition and classification of these neoplasms by the pathologist of utmost importance to determine prognosis, treatment, and follow-up strategies for affected patients.

Flynn A, Benn D, Clifton-Bligh R, et al.
The genomic landscape of phaeochromocytoma.
J Pathol. 2015; 236(1):78-89 [PubMed] Related Publications
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.

Dénes J, Swords F, Rattenberry E, et al.
Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.
J Clin Endocrinol Metab. 2015; 100(3):E531-41 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence.
OBJECTIVE: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL.
DESIGN: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples.
SETTING: The study was conducted at university hospitals.
PATIENTS: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study.
OUTCOME: Outcomes included genetic screening and clinical characteristics.
RESULTS: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context.
CONCLUSIONS: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Rao JU, Engelke UF, Sweep FC, et al.
Genotype-specific differences in the tumor metabolite profile of pheochromocytoma and paraganglioma using untargeted and targeted metabolomics.
J Clin Endocrinol Metab. 2015; 100(2):E214-22 [PubMed] Related Publications
CONTEXT AND OBJECTIVE: Pheochromocytomas and paragangliomas (PGLs) are neuroendocrine tumors of sympathetic or parasympathetic paraganglia. Nearly 40% of PGLs are caused by germline mutations. The present study investigated the effect of genetic alterations on metabolic networks in PGLs.
DESIGN: Homogenates of 32 sporadic PGLs and 48 PGLs from patients with mutations in SDHB, SDHD, SDHAF-2, VHL, RET, and NF-1 were subjected to proton ((1)H) nuclear magnetic resonance (NMR) spectroscopy at 500 MHz for untargeted and HPLC tandem mass spectrometry for targeted metabolite profiling.
RESULTS: (1)H NMR spectroscopy identified 28 metabolites in PGLs of which 12 showed genotype-specific differences. Part of these results published earlier reported low complex II activity (P < .0001) and low ATP/ADP/AMP content (P < .001) in SDH-related PGLs compared with sporadics and PGLs of other genotypes. Extending these results, low levels of N-acetylaspartic acid (NAA; P < .05) in SDH tumors and creatine (P < .05) in VHL tumors were observed compared with sporadics and other genotypes. Positive correlation was observed between NAA and ATP/ADP/AMP content (P < .001) and NAA and complex II activity (P < .0001) of PGLs. Targeted purine analysis in PGLs showed low adenine in cluster 1 compared with cluster 2 tumors (SDH P < .0001; VHL P < .05) whereas lower levels (P < .05) of guanosine and hypoxanthine were observed in RET tumors compared with SDH tumors. Principal component analysis (PCA) of metabolites could distinguish PGLs of different genotypes.
CONCLUSIONS: The present study gives a comprehensive picture of alterations in energy metabolism in SDH- and VHL-related PGLs and establishes the interrelationship of energy metabolism and amino acid and purine metabolism in PGLs.

Menara M, Oudijk L, Badoual C, et al.
SDHD immunohistochemistry: a new tool to validate SDHx mutations in pheochromocytoma/paraganglioma.
J Clin Endocrinol Metab. 2015; 100(2):E287-91 [PubMed] Related Publications
CONTEXT: Pheochromocytomas (PCC) and paragangliomas (PGL) may be caused by a germline mutation in 12 different predisposing genes. We previously reported that immunohistochemistry is a useful approach to detect patients harboring SDHx mutations. SDHA immunostaining is negative in SDHA-mutated tumors only, while SDHB immunostaining is negative in samples mutated on all SDHx genes. In some cases of SDHD or SDHC-mutated tumors, a weak diffuse SDHB labeling has however been described.
OBJECTIVE: Here, we addressed whether the same procedure could be applicable to detect patients with germline SDHD mutations, by testing two new commercially available anti-SDHD antibodies.
DESIGN AND METHODS: We performed a retrospective study on 170 PGL/PCC in which we investigated SDHD and SDHB expression by immunohistochemistry.
RESULTS: SDHx-mutated PGL/PCC showed a completely negative SDHB staining (23/27) or a weak cytoplasmic background (4/27). Unexpectedly, we observed that SDHD immunohistochemistry was positive in SDHx-deficient tumors and negative in the other samples. Twenty-six of 27 SDHx tumors (including the four weakly stained for SDHB) were positive for SDHD. Among non-SDHx tumors, 138/143 were positive for SDHB and negative for SDHD. Five cases showed a negative immunostaining for SDHB, but were negative for SDHD.
CONCLUSION: Our results demonstrate that a positive SDHD immunostaining predicts the presence of an SDHx gene mutation. Because SDHB negative immunostaining is sometimes difficult to interpret in the case of background, the addition of SDHD positive immunohistochemistry will be a very useful tool to predict or validate SDHx gene variants in PGL/PCC.

Toledo SP, Lourenço DM, Sekiya T, et al.
Penetrance and clinical features of pheochromocytoma in a six-generation family carrying a germline TMEM127 mutation.
J Clin Endocrinol Metab. 2015; 100(2):E308-18 [PubMed] Related Publications
CONTEXT: The phenotype of familial pheochromocytoma (PHEO) associated with germline TMEM127 mutations (TMEM127-related PHEO) has not been clearly defined.
OBJECTIVE: This study aimed to investigate the penetrance, full phenotypic spectrum and effectiveness of clinical/genetic screening in TMEM127-related PHEO.
DESIGN, SETTING, AND PARTICIPANTS: Clinical and genetic screening, and genetic counseling were offered to 151 individuals from a six-generation family carrying a TMEM127 germline mutation in a referral center.
INTERVENTION AND MAIN OUTCOME MEASURES: TMEM127 genetic testing was offered to at-risk relatives and clinical surveillance for pheochromocytoma was performed in mutation-positive carriers.
RESULTS: Forty seven individuals carried the c.410-2A>C TMEM127 mutation. Clinical data were obtained from 34 TMEM127-mutation carriers followed up for 8.7 ± 8.1 years (range, 1-20 y). Pheochromocytoma was diagnosed in 11 carriers (32%) at a median age of 43 years. In nine patients, symptoms started at 29 years (range, 10-55 y) and two cases were asymptomatic. Tumors were multicentric in five (45%) and bilateral in five (45%) patients. Six patients (54%) had at least one adrenomedullary nodule less than 10 mm. No paragangliomas, distant metastases, or other manifestations were detected. Cumulative penetrance of pheochromocytoma was 0% at 0-20 years, 3% at 21-30 years, 15% at 31-40 years, 24% at 41-50 years, and 32% at 51-65 years. The youngest case was diagnosed at 22 years and the earliest symptoms were reported at age 10.
CONCLUSIONS: Tumor multicentricity, nodular adrenomedullary hyperplasia, and the occurrence of symptoms more than a decade earlier than the age at diagnosis are novel findings in TMEM127-related PHEO. The high penetrance of pheochromocytoma in this condition validates the benefits of genetic testing of at-risk relatives. We thus recommend that TMEM127 genetic testing should be offered to at-risk individuals at age 22 years and mutation carriers should undergo clinical surveillance annually.

Macías D, Fernández-Agüera MC, Bonilla-Henao V, López-Barneo J
Deletion of the von Hippel-Lindau gene causes sympathoadrenal cell death and impairs chemoreceptor-mediated adaptation to hypoxia.
EMBO Mol Med. 2014; 6(12):1577-92 [PubMed] Free Access to Full Article Related Publications
Mutations of the von Hippel-Lindau (VHL) gene are associated with pheochromocytomas and paragangliomas, but the role of VHL in sympathoadrenal homeostasis is unknown. We generated mice lacking Vhl in catecholaminergic cells. They exhibited atrophy of the carotid body (CB), adrenal medulla, and sympathetic ganglia. Vhl-null animals had an increased number of adult CB stem cells, although the survival of newly generated neuron-like glomus cells was severely compromised. The effects of Vhl deficiency were neither prevented by pharmacological inhibition of prolyl hydroxylases or selective genetic down-regulation of prolyl hydroxylase-3, nor phenocopied by hypoxia inducible factor overexpression. Vhl-deficient animals appeared normal in normoxia but survived for only a few days in hypoxia, presenting with pronounced erythrocytosis, pulmonary edema, and right cardiac hypertrophy. Therefore, in the normal sympathoadrenal setting, Vhl deletion does not give rise to tumors but impairs development and plasticity of the peripheral O₂-sensing system required for survival in hypoxic conditions.

Garnier S, Réguerre Y, Orbach D, et al.
[Pediatric pheochromocytoma and paraganglioma: an update].
Bull Cancer. 2014; 101(10):966-75 [PubMed] Related Publications
Pheochromocytomas and paragangliomas (PHEO/PGL) are neuroendocrine tumors that arise from sympathetic and parasympathetic paraganglia. Although well described in the adult population, diagnosis and treatment of these exceptionally rare neoplasms remains poorly characterized in children. This article reviews recent advances in clinical presentation, genetics, biochemistry, imaging and treatment of children with benign or malignant PHEO/PGL. Compared to adults, pediatric PHEO/PGL are more frequently familial, bilateral, multifocal and malignant. Approximately 50% of pediatric PHEO/PGL are associated with a mutation of one of the 12 known susceptibility genes. Von Hippel-Lindau disease, type 1 neurofibromatosis, type 2 multiple endocrine neoplasia and familial PGL syndrome are hereditary tumor syndromes associated with an increased risk of developing such diseases. Clinical presentation includes symptoms related to catecholamine hypersecretion and/or tumor mass effect. Plasma and/or urine metanephrine dosages are recommended as first-line diagnostic biochemical tests. Magnetic resonance imaging is useful as initial radiological approach. Most pediatric PHEO/PGLs are benign. Surgical resection, with appropriate perioperative management of catecholamine-related symptoms, remains the treatment of choice. In case of metastatic disease, surgical removal of metastases when possible and I-131-MIBG radiotherapy provide limited results whereas chemotherapy is reserved for more advanced stages.

Couvé S, Ladroue C, Laine E, et al.
Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis.
Cancer Res. 2014; 74(22):6554-64 [PubMed] Related Publications
The classic model of tumor suppression implies that malignant transformation requires full "two-hit" inactivation of a tumor-suppressor gene. However, more recent work in mice has led to the proposal of a "continuum" model that involves more fluid concepts such as gene dosage-sensitivity and tissue specificity. Mutations in the tumor-suppressor gene von Hippel-Lindau (VHL) are associated with a complex spectrum of conditions. Homozygotes or compound heterozygotes for the R200W germline mutation in VHL have Chuvash polycythemia, whereas heterozygous carriers are free of disease. Individuals with classic, heterozygous VHL mutations have VHL disease and are at high risk of multiple tumors (e.g., CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma). We report here an atypical family bearing two VHL gene mutations in cis (R200W and R161Q), together with phenotypic analysis, structural modeling, functional, and transcriptomic studies of these mutants in comparison with classical mutants involved in the different VHL phenotypes. We demonstrate that the complex pattern of disease manifestations observed in VHL syndrome is perfectly correlated with a gradient of VHL protein (pVHL) dysfunction in hypoxia signaling pathways. Thus, by studying naturally occurring familial mutations, our work validates in humans the "continuum" model of tumor suppression.

Sue M, Martucci V, Frey F, et al.
Lack of utility of SDHB mutation testing in adrenergic metastatic phaeochromocytoma.
Eur J Endocrinol. 2015; 172(2):89-95 [PubMed] Related Publications
OBJECTIVE: Testing for succinate dehydrogenase subunit B (SDHB) mutations is recommended in all patients with metastatic phaeochromocytomas and paragangliomas (PPGLs), but may not be required when metastatic disease is accompanied by adrenaline production. This retrospective cohort study aimed to establish the prevalence of SDHB mutations among patients with metastatic PPGLs, characterised by production of adrenaline compared with those without production of adrenaline, and to establish genotype–phenotype features of metastatic PPGLs according to underlying gene mutations.
DESIGN AND METHODS: Presence of SDHB mutations or deletions was tested in 205 patients (114 males) aged 42+/-16 years (range 9–86 years) at diagnosis of metastatic PPGLs with and without adrenaline production.
RESULTS: Twenty-three of the 205 patients (11%) with metastatic PPGLs had disease characterised by production of adrenaline, as defined by increased plasma concentrations of metanephrine larger than 5% of the combined increase in both normetanephrine and metanephrine. None of these 23 patients had SDHB mutations. Of the other 182 patients with no tumoural adrenaline production, 51% had SDHB mutations. Metastases in bone were 36–41% more prevalent among patients with SDHB mutations or extra-adrenal primary tumours than those without mutations or with adrenal primary tumours. Liver metastases were 81% more prevalent among patients with adrenal than extra-adrenal primary tumours.
CONCLUSION: SDHB mutation testing has no utility among patients with adrenaline-producing metastatic PPGLs, but is indicated in other patients with metastatic disease. Our study also reveals novel associations of metastatic spread with primary tumour location and presence of SDHB mutations.

Bayley JP, Oldenburg RA, Nuk J, et al.
Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations.
BMC Med Genet. 2014; 15:111 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: 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.
METHODS: Here we explore the underlying molecular basis of three cases of paraganglioma or pheochromocytoma that came to our attention due to apparent maternal transmission of an SDHD mutation. We used DNA analysis of family members to establish the mode of inheritance of each mutation. Genetic and immunohistochemical studies of available tumors were then carried out to confirm SDHD-related tumorigenesis.
RESULTS: 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. The third case appears to be a phenocopy, a sporadic paraganglioma in an SDHD mutation carrier with no immunohistochemical or DNA evidence to support a causal link between the mutation and the tumor. Microsatellite analysis in the tumor of patient 1 provided evidence for somatic recombination and loss of the paternal region of chromosome 11 including SDHD and the maternal chromosome including the centromere and the p arm.
CONCLUSIONS: 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.

Igaz P, Igaz I, Nagy Z, et al.
MicroRNAs in adrenal tumors: relevance for pathogenesis, diagnosis, and therapy.
Cell Mol Life Sci. 2015; 72(3):417-28 [PubMed] Related Publications
Several lines of evidence support the relevance of microRNAs in both adrenocortical and adrenomedullary (pheochromocytomas) tumors. Significantly differentially expressed microRNAs have been described among benign and malignant adrenocortical tumors and different forms of pheochromocytomas that might affect different pathogenic pathways. MicroRNAs can be exploited as markers of malignancy or disease recurrence. Besides tissue microRNAs, novel data show that microRNAs are released in body fluids, and blood-borne microRNAs can be envisaged as minimally invasive markers of malignancy or prognosis. MicroRNAs might even serve as treatment targets that could expand the rather-limited therapeutic repertoire in the field of adrenal tumors. In this review, we present a critical synopsis of the recent observations made in the field of adrenal tumor-associated microRNAs regarding their pathogenic, diagnostic, and potential therapeutic relevance.

Zdrojowy-Wełna A, Bednarek-Tupikowska G
Challenges in the diagnosis of pheochromocytoma and paraganglioma syndrome.
Neuro Endocrinol Lett. 2014; 35(5):355-8 [PubMed] Related Publications
OBJECTIVES: Adrenal pheochromocytomas are rare neuroendocrine tumours, however their prevalence is probably underestimated - in some series 50% were diagnosed at autopsy. The clinical presentation varies among patients, that is why diagnosis might be difficult to establish. Pheochromocytoma may coexist with paraganglioma and when paraganglioma is diagnosed, the patient should be screened for pheochromocytoma too, especially in people with hypertension. We present a case of woman with pheochromocytoma, but diagnosed after incidence of stroke, who had also paraganglioma in the past. Additionally, a teratoma was diagnosed simultaneously.
CASE REPORT: 49-year old woman with hypertension was referred to the Department of Endocrinology, Diabetology and Isotope Therapy in Wrocław with suspected pheochromocytoma. She was operated twice because of paraganglioma of the right and left carotid artery, second operation was complicated with stroke. After administration of anticoagulants a bleeding from gastrointestinal tract occurred. During diagnostic process CT of the abdomen showed tumour in the right adrenal gland and a tumour in pelvis. Significantly elevated catecholamines and their metabolites in blood and urine confirmed the diagnosis of pheochromocytoma. Both tumours were removed surgically, the second was teratoma maturum. Genetic screening for hereditary pheochromocytoma was proceeded. A mutation in SDHD gene was revealed in patient's DNA and subsequently in blood samples of her sister and daughter.
CONCLUSIONS: Occurrence of paraganglioma with hypertension suggest need of screening for pheochromocytoma-paraganglioma syndrome, especially in case of paragangliomas in family history. Early treatment is crucial to avoid life-threatening cardiovascular complications. The association between pheochromocytoma and teratoma is unclear.

Kurisaki-Arakawa A, Saito T, Takahashi M, et al.
A case of (123)I-MIBG scintigram-negative functioning pheochromocytoma: immunohistochemical and molecular analysis with review of literature.
Int J Clin Exp Pathol. 2014; 7(7):4438-47 [PubMed] Free Access to Full Article Related Publications
A 70-year-old Japanese woman was referred to our hospital due to hyperhidrosis and rapid weight loss of 10 kg in a month. A lump measuring 26 mm in diameter was detected in the left adrenal gland by computed tomography. Biochemical tests showed high levels of serum and urinary norepinephrine and epinephrine. However, a (123)I-MIBG scintigram failed to detect any accumulation in the left adrenal tumor. A left adrenalectomy was performed post clinical diagnosis of (123)I-MIBG negative pheochromocytoma. Microscopically, the tumor exhibited pheochromocytoma compatible features. Immunohistochemical analysis revealed low expression of VMAT1 in the tumor compared to the normal, surrounding tissue. To test for a possible genetic alteration of the monoamine transporter genes, we performed whole-exome sequencing of the VMAT1, VMAT2, and NET genes in the tumor. No significant base sequence substitution or deletion/insertion was found in any transporter. This suggests that MIBG negativity is caused by a change that is independent of the base sequence abnormalities, such as an epigenetic change. Furthermore, a retrospective literature review of (123)I-MIBG negative-scintigraphy cases indicates that a negative finding in the (123)I-MIBG scintigram is frequently associated with metastatic pheochromocytomas or SDHB mutations. However, a SDHB/D gene mutation has not been identified in the reported case. Although the patient needs careful monitoring following the surgery, to date she has been disease free for 12 months. This study could not find clear reasons for negative conversion, however, investigations of the negative conversion mechanism might reveal significant insights towards the improvement of patient survival.

Corssmit EP, Romijn JA
Clinical management of paragangliomas.
Eur J Endocrinol. 2014; 171(6):R231-43 [PubMed] Related Publications
Paragangliomas (PGLs) are rare vascular, neuroendocrine tumors of paraganglia, which are associated with either sympathetic tissue in adrenal (pheochromocytomas (PCCs)) and extraadrenal (sympathetic paraganglioma (sPGLs)) locations or parasympathetic tissue of the head and neck paragangliomas (HNPGLs). As HNPGLs are usually benign and most tumors grow slowly, a wait-and-scan policy is often advised. However, their location in the close proximity to cranial nerves and vasculature may result in considerable morbidity due to compression or infiltration of the adjacent structures, necessitating balanced decisions between a wait-and-see policy and active treatment. The main treatment options for HNPGL are surgery and radiotherapy. In contrast to HNPGLs, the majority of sPGL/PCCs produces catecholamines, in advanced cases resulting in typical symptoms and signs such as palpitations, headache, diaphoresis, and hypertension. The state-of-the-art diagnosis and localization of sPGL/PCCs are based on measurement of plasma and/or 24-h urinary excretion of (fractionated) metanephrines and methoxytyramine (MT). sPGL/PCCs can subsequently be localized by anatomical (computed tomography and/or magnetic resonance imaging) and functional imaging studies (123I-metaiodobenzylguanidine-scintigraphy, 111In-pentetreotide scintigraphy, or positron emission tomography with radiolabeled dopamine or dihydroxyphenylalanine). Although most PGL/PCCs are benign, factors such as genetic background, tumor size, tumor location, and high MT levels are associated with higher rates of metastatic disease. Surgery is the only curative treatment. Treatment options for patients with metastatic disease are limited. PGL/PCCs have a strong genetic background, with at least one-third of all cases linked with germline mutations in 11 susceptibility genes. As genetic testing becomes more widely available, the diagnosis of PGL/PCCs will be made earlier due to routine screening of at-risk patients. Early detection of a familial PGL allows early detection of potentially malignant PGLs and early surgical treatment, reducing the complication rates of this operation.

Schovanek J, Martucci V, Wesley R, et al.
The size of the primary tumor and age at initial diagnosis are independent predictors of the metastatic behavior and survival of patients with SDHB-related pheochromocytoma and paraganglioma: a retrospective cohort study.
BMC Cancer. 2014; 14:523 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Succinate dehydrogenase subunit B (SDHB) mutations are associated with aggressive pheochromocytoma (PHEO)/paraganglioma (PGL) behavior, often resulting in metastatic disease and fatal outcomes. These tumors are often larger, extra-adrenal, and contain lower catecholamine concentrations than other hereditary PHEOs/PGLs. This study evaluated the size and age at diagnosis of primary SDHB-related PHEOs/PGLs as independent predictors of their metastatic behavior and outcome (survival).
METHODS: One hundred six patients with SDHB mutation-related PHEO/PGL were included in this retrospective study. The recorded largest diameters, locations, and patient ages at initial diagnosis of SDHB-related primary tumors were analyzed in the context of time to metastasis and patient survival.
RESULTS: First, the development of metastatic disease in patients with primary tumors ≥4.5 cm was significantly earlier than in patients with smaller tumors (P = 0.003). Second, patients with primary tumors larger than 5.5 cm also had worse overall survival than patients with smaller tumors (P = 0.008). Third, age at initial diagnosis was found to be an independent predictor of patient survival (PHEOs: P = 0.041; PGLs: P < 0.001). Fourth, we did not observe a significant difference in survival based on the specific SDHB mutations or patient sex.
CONCLUSION: Receiver operating characteristic curves established 4.5 cm as the best value to dichotomize the primary SDHB-related PHEO/PGL in order to evaluate the development of metastatic disease and 5.5 cm as the best value for survival prediction. Subsequently, the size of the primary tumor was found as an age-independent predictor of patient survival and metastases development in PGL. In both PHEO and PGL, age at diagnosis was found to be a size-independent predictor of patient survival. No significant difference was found in metastases development or patient survival between males and females or among specific SDHB mutations. This data further extends and supports previous recommendations that carriers with SDHB mutations must undergo early and regular evaluations to detect PHEO/PGL in order to achieve the best clinical outcome.

Jain M, Zhang L, Boufraqech M, et al.
ZNF367 inhibits cancer progression and is targeted by miR-195.
PLoS One. 2014; 9(7):e101423 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Several members of the zinc finger protein family have been recently shown to have a role in cancer initiation and progression. Zinc finger protein 367 (ZNF367) is a member of the zinc finger protein family and is expressed in embryonic or fetal erythroid tissue but is absent in normal adult tissue.
METHODOLOGY/PRINCIPAL FINDINGS: We show that ZNF367 is overexpressed in adrenocortical carcinoma, malignant pheochromocytoma/paraganglioma and thyroid cancer as compared to normal tissue and benign tumors. Using both functional knockdown and ectopic overexpression in multiple cell lines, we show that ZNF367 inhibits cellular proliferation, invasion, migration, and adhesion to extracellular proteins in vitro and in vivo. Integrated gene and microRNA expression analyses showed an inverse correlation between ZNF367 and miR-195 expression. Luciferase assays demonstrated that miR-195 directly regulates ZNF367 expression and that miR-195 regulates cellular invasion. Moreover, integrin alpha 3 (ITGA3) expression was regulated by ZNF367.
CONCLUSIONS/SIGNIFICANCE: Our findings taken together suggest that ZNF367 regulates cancer progression.

van Hulsteijn LT, Niemeijer ND, Hes FJ, et al.
Phenotype of SDHB mutation carriers in the Netherlands.
Fam Cancer. 2014; 13(4):651-7 [PubMed] Related Publications
SDHB mutation carriers are predisposed to developing paragangliomas (PGLs). The objective of this study was to assess genotype-phenotype correlations of a Dutch cohort of SDHB mutation carriers and assess potential differences in clinical phenotypes related to specific SDHB founder mutations. Forty-seven consecutive SDHB mutation carriers were included. Initial screening consisted of measurement of 24 h urinary excretion of catecholamines and their metabolites in duplicate, repeated annually if initial biochemical screening was negative. Whole-body imaging studies with magnetic resonance imaging (MRI) or computed tomography (CT) and/or (123)I-MIBG scintigraphy were performed in case of catecholamine excess, and MRI or CT scans of thorax, abdomen and pelvis were performed every 2 years regardless of catecholamine levels. Repetitive head-and-neck MRI was performed at 2 year intervals. Mean follow-up was 3.6 ± 3.6 years. Twenty-seven persons (57 %) carried the SDHB c.423+1 G>A mutation and seven persons (15 %) the SDHB c.201-4429_287-933del (exon 3 deletion) mutation. No differences were found in the clinical phenotype of carriers of these two specific SDHB mutations. By end of follow-up, 49 % of SDHB mutation carriers displayed no biochemical or radiological evidence of manifest disease, i.e. they were unaffected carriers. Three persons (6 %) had been diagnosed with a pheochromocytoma (PCC), four with a sympathetic PGL (sPGL) (9 %), 18 with a HNPGL (38 %), and two persons (4 %) had developed a malignant paraganglioma, i.e. metastatic disease. In conclusion, the two main Dutch SDHB founder mutations do not differ in clinical expression and result in a relatively mild phenotype. Over one-third of SDHB mutation carriers develop HNPGL, with sPGL/PCC in only 15 % and malignancy in only 4 %.

Richter S, Peitzsch M, Rapizzi E, et al.
Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency.
J Clin Endocrinol Metab. 2014; 99(10):3903-11 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
CONTEXT: Mutations of succinate dehydrogenase A/B/C/D genes (SDHx) increase susceptibility to development of pheochromocytomas and paragangliomas (PPGLs), with particularly high rates of malignancy associated with SDHB mutations.
OBJECTIVE: We assessed whether altered succinate dehydrogenase product-precursor relationships, manifested by differences in tumor ratios of succinate to fumarate or other metabolites, might aid in identifying and stratifying patients with SDHx mutations.
DESIGN, SETTING, AND PATIENTS: PPGL tumor specimens from 233 patients, including 45 with SDHx mutations, were provided from eight tertiary referral centers for mass spectrometric analyses of Krebs cycle metabolites.
MAIN OUTCOME MEASURE: Diagnostic performance of the succinate:fumarate ratio for identification of pathogenic SDHx mutations.
RESULTS: SDH-deficient PPGLs were characterized by 25-fold higher succinate and 80% lower fumarate, cis-aconitate, and isocitrate tissue levels than PPGLs without SDHx mutations. Receiver-operating characteristic curves for use of ratios of succinate to fumarate or to cis-aconitate and isocitrate to identify SDHx mutations indicated areas under curves of 0.94 to 0.96; an optimal cut-off of 97.7 for the succinate:fumarate ratio provided a diagnostic sensitivity of 93% at a specificity of 97% to identify SDHX-mutated PPGLs. Succinate:fumarate ratios were higher in both SDHB-mutated and metastatic tumors than in those due to SDHD/C mutations or without metastases.
CONCLUSIONS: Mass spectrometric-based measurements of ratios of succinate:fumarate and other metabolites in PPGLs offer a useful method to identify patients for testing of SDHx mutations, with additional utility to quantitatively assess functionality of mutations and metabolic factors responsible for malignant risk.

Shokoohinia Y, Hosseinzadeh L, Moieni-Arya M, et al.
Osthole attenuates doxorubicin-induced apoptosis in PC12 cells through inhibition of mitochondrial dysfunction and ROS production.
Biomed Res Int. 2014; 2014:156848 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Doxorubicin (DOX) is a potent, broad-spectrum chemotherapeutic drug used for treatment of several types of cancers. Despite its effectiveness, it has a wide range of toxic side effects, many of which most likely result from its inherent prooxidant activity. It has been reported that DOX has toxic effects on normal tissues, including brain tissue. In the current study, we investigated the protective effect of osthole isolated from Prangos ferulacea (L.) Lindl. on oxidative stress and apoptosis induced by DOX in PC12 as a neuronal model cell line. PC12 cells were pretreated with osthole 2 h after treatment with different concentrations of DOX. 24 h later, the cell viability, mitochondrial membrane potential (MMP), the activity of caspase-3, the expression ratio of Bax/Bcl-2, and the generation of intracellular ROS were detected. We found that pretreatment with osthole on PC12 cells significantly reduced the loss of cell viability, the activity of caspase-3, the increase in Bax/Bcl-2 ratio, and the generation of intracellular ROS induced by DOX. Moreover, pretreatment with osthole led to an increase in MMP in PC12 cells. In conclusion, our results indicated that pretreatment with nontoxic concentrations of osthole protected PC12 cells from DOX-mediated apoptosis by inhibition of ROS production.

Clark GR, Sciacovelli M, Gaude E, et al.
Germline FH mutations presenting with pheochromocytoma.
J Clin Endocrinol Metab. 2014; 99(10):E2046-50 [PubMed] Related Publications
CONTEXT: At least a third of the patients with pheochromocytoma (PCC) or paraganglioma (PGL) harbor an underlying germline mutation in a known PCC/PGL gene. Mutations in genes (SDHB, SDHD, SDHC, and SDHA) encoding a component of the tricarboxylic acid cycle, succinate dehydrogenase (SDH), are a major cause of inherited PCC and PGL. SDHB mutations are also, albeit less frequently, associated with inherited renal cell carcinoma. Inactivation of SDH and another tricarboxylic acid cycle component, fumarate hydratase (FH), have both been associated with abnormalities of cellular metabolism, responsible for the activation of hypoxic gene response pathways and epigenetic alterations (eg, DNA methylation). However, the clinical phenotype of germline mutations in SDHx genes and FH is usually distinct, with FH mutations classically associated with hereditary cutaneous and uterine leiomyomatosis and renal cell carcinoma, although recently an association with PCC/PGL has been reported.
OBJECTIVE AND DESIGN: To identify potential novel PCC/PGL predisposition genes, we initially undertook exome resequencing studies in a case of childhood PCC, and subsequently FH mutation analysis in a further 71 patients with PCC, PGL, or head and neck PGL.
RESULTS: After identifying a candidate FH missense mutation in the exome study, we then detected a further candidate missense mutation (p.Glu53Lys) by candidate gene sequencing. In vitro analyses demonstrated that both missense mutations (p.Cys434Tyr and p.Glu53Lys) were catalytically inactive.
CONCLUSIONS: These findings 1) confirm that germline FH mutations may present, albeit rarely with PCC or PGL; and 2) extend the clinical phenotype associated with FH mutations to pediatric PCC.

Daly AF, Beckers A
A bittersweet symphony.
Endocr Relat Cancer. 2014; 21(4):C7-9 [PubMed] Related Publications
This issue analyzes new work expanding the range of how genetic dysregulation of succinate dehydrogenase subunit (SDHx) genes can cause cancer syndromes with a prominent endocrine component, in this case Carney triad, which is characterized by gastrointestinal stromal tumors, paraganglioma, and pulmonary chondromas.

Borroni RG, Grassi S, Diegoli M, et al.
Incomplete penetrance of GLMN gene c.395-1G>C mutation in a family with glomuvenous malformations.
Int J Dermatol. 2014; 53(11):1362-4 [PubMed] Related Publications
Glomuvenous malformations (GVMs, OMIM 138000) are hamartomas presenting in childhood as multiple, bluish, soft papules and nodules that tend to grow slowly in size and number with age. They are caused by autosomal dominant mutations in glomulin (GLMN) gene; penetrance varies from 80% at 20 to about 100% at age 30 years. We report on the c.395-1G>C mutation of GLMN gene in two siblings showing variable penetrance.

Papathomas TG, Oudijk L, Zwarthoff EC, et al.
Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia.
Endocr Relat Cancer. 2014; 21(4):653-61 [PubMed] Related Publications
Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (P=0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact tumors. We conclude that TERT promoter mutations occur in ACCs and ea PGLs. In addition, preliminary evidence indicates a potential association with the acquisition of TERT promoter mutations in SDH-deficient tumors.

Jochmanová I, Zelinka T, Widimský J, Pacak K
HIF signaling pathway in pheochromocytoma and other neuroendocrine tumors.
Physiol Res. 2014; 63 Suppl 2:S251-62 [PubMed] Related Publications
Hypoxia-inducible factors (HIFs) are transcription factors controlling energy, iron metabolism, erythropoiesis, and development. Dysregulation of these proteins contributes to tumorigenesis and cancer progression. Recent findings revealed the important role of HIFs in the pathogenesis of neuroendocrine tumors, especially pheochromocytoma (PHEO) and paraganglioma (PGL). PHEOs and PGLs are catecholamine-producing tumors arising from sympathetic- or parasympathetic-derived chromaffin tissue. To date, eighteen PHEO/PGL susceptibility genes have been identified. Based on the main signaling pathways, PHEOs/PGLs have been divided into two clusters, pseudohypoxic cluster 1 and cluster 2, rich in kinase receptor signaling and protein translation pathways. Recent data suggest that both clusters are interconnected via the HIF signaling and its role in tumorigenesis is supported by newly described somatic and germline mutations in HIF2A gene in patients with PHEOs/PGLs associated with polycythemia, and in some of them also with somatostatinoma. Moreover, HIFalpha signaling has also been shown to be upregulated in neuroendocrine tumors other than PHEO/PGL. Some of these tumors are components of hereditary tumor syndromes which can be associated with PHEO/PGL, but also in ileal carcinoids or melanoma. HIF signaling appears to be one of the crucial players in tumorigenesis, which could suggest new therapeutic approaches for treatment of neuroendocrine tumors.

Haller F, Moskalev EA, Faucz FR, et al.
Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad.
Endocr Relat Cancer. 2014; 21(4):567-77 [PubMed] Related Publications
Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney-Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism of tumorigenesis in CT.

Makuch E, Kuropatwa M, Kurowska E, et al.
Phosphodiesterase 2 negatively regulates adenosine-induced transcription of the tyrosine hydroxylase gene in PC12 rat pheochromocytoma cells.
Mol Cell Endocrinol. 2014; 392(1-2):51-9 [PubMed] Related Publications
Adenosine induces expression of the tyrosine hydroxylase (TH) gene in PC12 cells. However, it is suggested that atrial natriuretic peptide (ANP) inhibits expression of this gene. Using real-time PCR and luciferase reporter assays we found that ANP significantly decreases the adenosine-induced transcription of the TH gene. Results of measurements of cyclic nucleotide concentrations indicated that ANP-induced accumulation of cGMP inhibits the adenosine-induced increase in cAMP level. Using selective phosphodiesterase 2 (PDE2) inhibitors and a synthetic cGMP analog activating PDE2, we found that PDE2 is involved in coupling the ANP-triggered signal to the cAMP metabolism. We have established that ANP-induced elevated levels of cGMP as well as cGMP analog stimulate hydrolytic activity of PDE2, leading to inhibition of adenosine-induced transcription of the TH gene. We conclude that ANP mediates negative regulation of TH gene expression via stimulation of PDE2-dependent cAMP breakdown in PC12 cells.

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