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Identification of Potential Gene Markers and Insights into the Pathophysiology of Pheochromocytoma Malignancy

Institut National de la Santé et de la Recherche Médicale U413 (E.T., J.G., A.P., H.G., L.G., H.L., H.V., L.Y., Y.A.), Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (Institut Fédératif de Recherche Multidisciplinaires sur les Peptides 23), University of Rouen, 76821 Mont-Saint-Aignan, France; Genome Technology Branch (A.G.E.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Department of Genetics (A.-P.G.-R.), Hôpital Européen Georges Pompidou, 75015 Paris, France; Department of Endocrinology (J.B.), Institut National de la Santé et de la Recherche Médicale U567, Institut Cochin, 75014 Paris, France; Department of Endocrinology (M.M., M.K.), Hôpital de Brabois, 54511 Nancy, France; Equipe Mixte Institut National de la Santé et de la Recherche Médicale EMI 0359 (L.O.), Laboratory of Experimental Cancerology, Université de la Mediterranée, Aix-Marseille II, 13015 Marseille, France; and Hypertension Unit (P.-F.P.), Hôpital Européen Georges Pompidou, AP-HP, University of Paris-5, 75015 Paris, France

Address all correspondence and requests for reprints to: Dr. Y. Anouar, Institut National de la Santé et de la Recherche Médicale U413, Laboratory of Cellular and Molecular Neuroendocrinology, Institut Fédératif de Recherche Multidisciplinaires sur les Peptides 23, University of Rouen, 76821 Mont-Saint-Aignan, France. E-mail: youssef.anouar{at}univ-rouen.fr.

Context: Pheochromocytomas are catecholamine-producing tumors that are generally benign but that can also present as or develop into malignancy. Occurrence of malignant pheochromocytomas can only be asserted by imaging of metastatic lesions.

Objectives: We conducted a gene expression profiling of benign and malignant tumors to identify a gene signature that would allow us to discriminate benign from malignant pheochromocytomas and to gain a better understanding of tumorigenic pathways associated with malignancy.

Design: A total of 36 patients with pheochromocytoma was studied retrospectively. There were 18 (nine benign and nine malignant) tumors used for gene expression profiling on pangenomic oligonucleotide microarrays.

Results: We identified and validated a set of predictor genes that could accurately distinguish the two tumor subtypes through unsupervised clustering. Most of the differentially expressed genes were down-regulated in malignant tumors, and several of these genes encoded neuroendocrine factors involved in prominent characteristics of chromaffin cell biology. In particular, the expression of two key processing enzymes of trophic peptides, peptidylglycine -amidating monooxygenase and glutaminyl-peptide cyclotransferase, was reduced in malignant pheochromocytomas.

Conclusion: The gene expression profiling of benign and malignant pheochromocytomas clearly identified a set of genes that could be used as a prognostic multi-marker and revealed that the expression of several genes encoding neuroendocrine proteins was reduced in malignant compared with benign tumors.

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