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Judith Favier,
Peter Igaz,
Nelly Burnichon,
Laurence Amar,
Rossella Libé, Cécile Badoual,
Frédérique Tissier,
Jérôme Bertherat,
Pierre-François Plouin,
Xavier Jeunemaitre,
Anne-Paule Gimenez-Roqueplo
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ABSTRACT: Pheochromocytomas and paragangliomas are highly vascularized tumors which are candidates for anti-angiogenic therapies. Several studies have reported the association of vascular endothelial growth factor (VEGF) overexpression with malignancy, but none took into account the genetic status of the patients or tumors, which may have a major influence on such observations. Transcriptome studies indeed revealed that pheochromocytomas and paragangliomas can be classified into two major clusters depending on their gene expression profile: Cluster 1 comprises samples associated with a hypoxic signature such as SDHx- and VHL-related tumors and cluster 2 includes RET, NF1, and TMEM127-mutated tumors, as well as most of sporadic tumors. The aim of this study was to provide a comprehensive rationale for the targeting of angiogenesis in patients with malignant forms of the disease. We used in situ hybridization, immunohistochemistry, and microarray gene expression profiling to evaluate angiogenesis and the expression of several angiogenic factors in a large cohort of pheochromocytomas and paragangliomas. We also studied the activation of mTOR by assessing the phosphorylation of its targets, P70 S6 kinase and 4E-BP1. These results were correlated with both malignancy and transcription signature. Our results reveal that cluster 1 tumors display a marked increase in both vascularization and in the expression of major angiogenic molecules, including VEGF, its receptors, HIF2α, Angiopoietin-2, and the endothelin receptors ETA and ETB. These overexpressions were observed in both benign and malignant samples of cluster 1 and thus appeared to be mainly dependent on the pseudo-hypoxic status of these tumors. The mTOR pathway was potentially activated in half of the tumors studied, with a slight increase in cluster 2 pheochromocytomas. Our results suggest that there is a strong rationale for anti-VEGF-based therapeutic strategies in malignant pheochromocytomas and paragangliomas, in particular in those associated with mutations in the SDHB gene.
Endocrine Pathology 12/2011; 23(1):34-42. · 1.36 Impact Factor
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Esther Korpershoek,
Judith Favier,
José Gaal,
Nelly Burnichon,
Bram van Gessel,
Lindsey Oudijk, Cécile Badoual,
Noémie Gadessaud,
Annabelle Venisse,
Jean-Pierre Bayley,
Marieke F van Dooren,
Wouter W de Herder,
Frédérique Tissier,
Pierre-François Plouin,
Francien H van Nederveen,
Winand N M Dinjens,
Anne-Paule Gimenez-Roqueplo,
Ronald R de Krijger
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ABSTRACT: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA.
In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations.
This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France).
We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA. Results: Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C → T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C → T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations.
Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas.
The Journal of clinical endocrinology and metabolism 07/2011; 96(9):E1472-6. · 6.50 Impact Factor
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Francien H van Nederveen,
José Gaal,
Judith Favier,
Esther Korpershoek,
Rogier A Oldenburg,
Elly M C A de Bruyn,
Hein F B M Sleddens,
Pieter Derkx,
Julie Rivière,
Hilde Dannenberg, [......],
Eric Van Marck,
Francesco Ferrau,
Jerney François,
Wouter W de Herder,
Mark-Paul F M Vrancken Peeters,
Anne van Linge,
Jacques W M Lenders,
Anne-Paule Gimenez-Roqueplo,
Ronald R de Krijger,
Winand N M Dinjens
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ABSTRACT: Phaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma-paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma-paraganglioma syndrome is often unrecognised, although 10-30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma-paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series.
Immunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing.
SDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87-100) and 84% (60-97), respectively.
Phaeochromocytoma-paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure. SDHB, SDHC, and SDHD germline mutation testing is indicated only in patients with SDHB-negative tumours. SDHB immunohistochemistry on phaeochromocytomas and paragangliomas could improve the diagnosis of phaeochromocytoma-paraganglioma syndrome.
The Netherlands Organisation for Scientific Research, Dutch Cancer Society, Vanderes Foundation, Association pour la Recherche contre le Cancer, Institut National de la Santé et de la Recherche Médicale, and a PHRC grant COMETE 3 for the COMETE network.
The lancet oncology 09/2009; 10(8):764-71. · 14.47 Impact Factor
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Judith Favier,
Jean-Jacques Brière,
Nelly Burnichon,
Julie Rivière,
Laure Vescovo,
Paule Benit,
Isabelle Giscos-Douriez,
Aurélien De Reyniès,
Jérôme Bertherat, Cécile Badoual,
Frédérique Tissier,
Laurence Amar,
Rosella Libé,
Pierre-François Plouin,
Xavier Jeunemaitre,
Pierre Rustin,
Anne-Paule Gimenez-Roqueplo
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ABSTRACT: The Warburg effect describes how cancer cells down-regulate their aerobic respiration and preferentially use glycolysis to generate energy. To evaluate the link between hypoxia and Warburg effect, we studied mitochondrial electron transport, angiogenesis and glycolysis in pheochromocytomas induced by germ-line mutations in VHL, RET, NF1 and SDH genes. SDH and VHL gene mutations have been shown to lead to the activation of hypoxic response, even in normoxic conditions, a process now referred to as pseudohypoxia. We observed a decrease in electron transport protein expression and activity, associated with increased angiogenesis in SDH- and VHL-related, pseudohypoxic tumors, while stimulation of glycolysis was solely observed in VHL tumors. Moreover, microarray analyses revealed that expression of genes involved in these metabolic pathways is an efficient tool for classification of pheochromocytomas in accordance with the predisposition gene mutated. Our data suggest an unexpected association between pseudohypoxia and loss of p53, which leads to a distinct Warburg effect in VHL-related pheochromocytomas.
PLoS ONE 01/2009; 4(9):e7094. · 4.09 Impact Factor
