We have investigated genetic/pathogenetic factors associated with a new clinical entity in patients presenting with pheochromocytoma/paraganglioma (PHEO/PGL) and polycythemia. Two patients without ...hypoxia-inducible factor 2α (
HIF2A
) mutations, who presented with similar clinical manifestations, were analyzed for other gene mutations, including prolyl hydroxylase (
PHD
) mutations. We have found for the first time a germ-line mutation in
PHD1
in one patient and a novel germ-line
PHD2
mutation in a second patient. Both mutants exhibited reduced protein stability with substantial quantitative protein loss and thus compromised catalytic activities. Due to the unique association of patients’ polycythemia with borderline or mildly elevated erythropoietin (EPO) levels, we also performed an in vitro sensitivity assay of erythroid progenitors to EPO and for EPO receptor (EPOR) expression. The results show inappropriate hypersensitivity of erythroid progenitors to EPO in these patients, indicating increased EPOR expression/activity. In addition, the present study indicates that HIF dysregulation due to
PHD
mutations plays an important role in the pathogenesis of these tumors and associated polycythemia. The
PHD1
mutation appears to be a new member contributing to the genetic landscape of this novel clinical entity. Our results support the existence of a specific
PHD1
- and
PHD2
-associated PHEO/PGL-polycythemia disorder.
Key message
• A novel germ-line
PHD1
mutation causing pheochromocytoma/paraganglioma and polycythemia.
• Increased EPOR activity and inappropriate hypersensitivity of erythroid progenitors to EPO.
Metastatic paraganglioma Fliedner, Stephanie M J; Lehnert, Hendrik; Pacak, Karel
Seminars in oncology,
12/2010, Letnik:
37, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Paragangliomas (PGLs) are chromaffin cell tumors arising from ganglia; when arising in the adrenal gland they are called pheochromocytomas. In recent years the opinion that metastatic disease is rare ...in PGL had to be revised, particularly in patients presenting with extra-adrenal PGL, with PGLs exceeding 5 cm in diameter, and/or those carrying an SDHB germline mutation. Metastases are expected to be present at the time of diagnosis in more than 10% of these patients. Measurement of plasma and urinary metanephrine levels is well established in diagnosing PGL. Recently, a dopaminergic phenotype (excess dopamine or methoxytyramine) was recognized as a good indicator of metastatic disease. Vast progress in targeted positron emission tomography (PET) imaging (eg, (18)F-FDA, (18)F-FDOPA, (18)F-FDG) now allows for reliable early detection of metastatic disease. However, once metastases are present, treatment options are limited. Survival of patients with metastatic PGL is variable, and frequently short. Here we review recent advances involving findings about the genetic background, the molecular pathogenesis, new diagnostic indicators, pathologic markers, and emerging treatment options for metastatic PGL.
The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a ...large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.
To date, germline or somatic genetic events can be detected for at least 60% of paragangliomas. Strong genotype–phenotype associations have been recognized and become increasingly refined. ...Characteristics closely linked with genotype include syndromic presentation, age of onset, risk of metastatic disease and predominant anatomic site. In contrast, profiles of catecholamine secretion appear to be largely determined by anatomic location or cell type of origin. This review summarizes current knowledge of genotype–phenotype correlations for paragangliomas in different locations and scrutinizes previous publications on the respective tissues of origin to find potential explanations for site-related differences. We hypothesize that differential sensitivities of distinct chromaffin cell populations to hypoxia are major determinants of these differences, with increased sensitivity to hypoxia likely exacerbating vulnerability to mutation-derived disruption of hypoxic signaling pathways. Potential involvement of endothelin-1, tumor necrosis factor type 1 receptor-associated protein and the hypoxia-inducible miR-210 in the development of abdomino-thoracic or head and neck paragangliomas are discussed. Recognition of factors that predispose to chromosomal losses, or amplify sub-threshold molecular alterations towards tumorigenic events in different (chromaffin) cell types, may facilitate the leap from developing targeted therapies towards establishment of tumor preventative measures.
Abstract
Context
Pheochromocytomas and paragangliomas (PPGLs) are characterized by distinct genotype-phenotype relationships according to studies largely restricted to Caucasian populations.
...Objective
To assess for possible differences in genetic landscapes and genotype-phenotype relationships of PPGLs in Chinese versus European populations.
Design
Cross-sectional study.
Setting
2 tertiary-care centers in China and 9 in Europe.
Participants
Patients with pathologically confirmed diagnosis of PPGL, including 719 Chinese and 919 Europeans.
Main Outcome Measures
Next-generation sequencing performed in tumor specimens with mutations confirmed by Sanger sequencing and tested in peripheral blood if available. Frequencies of mutations were examined according to tumor location and catecholamine biochemical phenotypes.
Results
Among all patients, higher frequencies of HRAS, FGFR1, and EPAS1 mutations were observed in Chinese than Europeans, whereas the reverse was observed for NF1, VHL, RET, and SDHx. Among patients with apparently sporadic PPGLs, the most frequently mutated genes in Chinese were HRAS (16.5% 13.6-19.3 vs 9.8% 7.6-12.1) and FGFR1 (9.8% 7.6-12.1 vs 2.2% 1.1-3.3), whereas among Europeans the most frequently mutated genes were NF1 (15.9% 13.2-18.6 vs 6.6% 4.7-8.5) and SDHx (10.7% 8.4–13.0 vs 4.2% 2.6–5.7). Among Europeans, almost all paragangliomas lacked appreciable production of epinephrine and identified gene mutations were largely restricted to those leading to stabilization of hypoxia inducible factors. In contrast, among Chinese there was a larger proportion of epinephrine-producing paragangliomas, mostly due to HRAS and FGFR1 mutations.
Conclusions
This study establishes Sino-European differences in the genetic landscape and presentation of PPGLs, including ethnic differences in genotype-phenotype relationships indicating a paradigm shift in our understanding of the biology of these tumors.
Background
Ganglioneuromas are very rare tumours of the sympathetic nervous system. Clinical and pathological knowledge is currently based on largely incomparable registries and case series that ...focus on paediatric or adrenal cases. To comprehensively characterize the full clinical spectrum across ages and locations, a meta‐analysis was performed where amenable and complemented by systematic literature review of individual patient data (IPD).
Design
Articles containing “ganglioneuroma” in English on humans, published from 1/1/1995‐6/27/2018, were identified from PubMed. Aggregate data from 10 eligible patient series on 19 variables were considerably inhomogeneous, restricting meta‐analysis to age and gender distribution. To determine basic disease characteristics across ages and locations, IPD were retrieved from case reports and small case series (PROSPERO CRD42018010247).
Results
Individual patient data representing 364 cases revealed that 65.7% (60.6%‐70.4%) were diagnosed in adults, more frequently in females (62%, 56.9%‐66.9%). 24.5% (20.3%‐39.1%) were discovered incidentally. Most often, ganglioneuromas developed in abdomen/pelvis (66.2, 32.1% adrenal). With age, the proportion of ganglioneuroma localizations with high post‐surgical complication rate (35.6% head/neck and 16.3% thorax) decreased. Contrarily, the diagnosis of adrenal ganglioneuromas (<1% post‐surgical complications) increased with age. Hormone production, hypertension or coincidence with another non‐neuroblastic neural‐crest‐derived tumour component was more common for adrenal location. Recurrence and metastatic spread have not been reported for ganglioneuromas without secondary tumour component.
Conclusions
This work summarizes characteristics of the currently largest number of international GN patients across all ages. The data confirm a benign nature of GN, independent of age. Age‐related differences in predominant tumour location, associated post‐surgical complications and hormone production suggest case‐centred management strategies.
Abstract
Context
Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin ...receptor 2 (SSTR2)–dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors.
Objective
Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs.
Methods
Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical–pathological features of PPGLs.
Results
Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line “cold” somatostatin analogs 100% (n = 6, n = 3 SDHx).
Conclusion
SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor–based therapies in metastatic PPGLs.
To date, malignant pheochromocytomas and paragangliomas (PHEOs/PGLs) cannot be effectively cured and thus novel treatment strategies are urgently needed. Lovastatin has been shown to effectively ...induce apoptosis in mouse PHEO cells (MPC) and the more aggressive mouse tumor tissue-derived cells (MTT), which was accompanied by decreased phosphorylation of mitogen-activated kinase (MAPK) pathway players. The MAPK pathway plays a role in numerous aggressive tumors and has been associated with a subgroup of PHEOs/PGLs, including K-RAS-, RET-, and NF1-mutated tumors. Our aim was to establish whether MAPK signaling may also play a role in aggressive, succinate dehydrogenase (SDH) B mutation-derived PHEOs/PGLs. Expression profiling and western blot analysis indicated that specific aspects of MAPK-signaling are active in SDHB PHEOs/PGLs, suggesting that inhibition by statin treatment could be beneficial. Moreover, we aimed to assess whether the anti-proliferative effect of lovastatin on MPC and MTT differed from that exerted by fluvastatin, simvastatin, atorvastatin, pravastatin, or rosuvastatin. Simvastatin and fluvastatin decreased cell proliferation most effectively and the more aggressive MTT cells appeared more sensitive in this respect. Inhibition of MAPK1 and 3 phosphorylation following treatment with fluvastatin, simvastatin, and lovastatin was confirmed by western blot. Increased levels of CASP-3 and PARP cleavage confirmed induction of apoptosis following the treatment. At a concentration low enough not to affect cell proliferation, spontaneous migration of MPC and MTT was significantly inhibited within 24 hours of treatment. In conclusion, lipophilic statins may present a promising therapeutic option for treatment of aggressive human paragangliomas by inducing apoptosis and inhibiting tumor spread.
Mutations of succinate dehydrogenase subunit B (SDHB) play a crucial role in the pathogenesis of the most aggressive and metastatic pheochromocytomas (PHEOs) and paragangliomas (PGLs). Although a ...variety of missense mutations in the coding sequence of the SDHB gene have been found in PHEOs and PGLs, it has been unclear whether these mutations impair mRNA expression, protein stability, subcellular localization, or intrinsic protein function. RT‐PCR and Western blot analysis of SDHB mRNA and protein expression from SDHB‐related PHEOs and PGLs demonstrated intact mRNA expression but significantly reduced protein expression compared to non‐SDHB PHEOs and PGLs. A pulse‐chase assay of common SDHB missense mutations in transfected HeLa cell lines demonstrated that the loss of SDHB function was due to a reduction in mutant protein half‐life, whereas colocalization of SDHB with mitochondria and immunoprecipitation with SDHA demonstrated intact subcellular localization and complex formation. The half‐life of the SDHB protein increased after treatment with histone deacetylase inhibitors (HDACis), implicating the protein quality control machinery in the degradation of mutant SDHB protein. These findings provide the first direct mechanism of functional loss resulting from SDHB mutations and suggest that reducing protein degradation with HDACis may serve as a novel therapeutic paradigm for preventing the development of SDHB‐related tumors.—Yang, C., Matro, J. C., Huntoon, K. M., Ye, D. Y., Huynh, T. T., Fliedner, S. M. J., Breza, J., Zhuang, Z., Pacak, K. Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function. FASEB J. 26, 4506–4516 (2012). www.fasebj.org
PDF
