Identification of potential gene markers and insights into the pathophysiology of pheochromocytoma malignancy.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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 alpha-amidating monooxygenase and glutaminyl-peptide cyclotransferase, was reduced in malignant pheochromocytomas.


CONCLUSIONS
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.
Thouënnon
Erwan
E
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.
Elkahloun
Abdel G
AG
Guillemot
Johann
J
Gimenez-Roqueplo
Anne-Paule
AP
Bertherat
Jérôme
J
Pierre
Alice
A
Ghzili
Hafida
H
Grumolato
Luca
L
Muresan
Mihaela
M
Klein
Marc
M
Lefebvre
Hervé
H
Ouafik
L'Houcine
L
Vaudry
Hubert
H
Plouin
Pierre-François
PF
Yon
Laurent
L
Anouar
Youssef
Y
D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
D005819:Genetic Markers; D012334:RNA, Neoplasm