Expression of Contactin 4 is associated with malignant behavior in pheochromocytomas and paragangliomas.

Evenepoel, Lucie; van Nederveen, Francien H; Oudijk, Lindsey; Papathomas, Thomas G; Restuccia, David F; Belt, Eric J T; de Herder, Wouter W; Feelders, Richard A; Franssen, Gaston J H; Hamoir, Marc; Maiter, Dominique; Perren, Aurel; Timmers, Henri J L M; van Eeden, Susanne; Vroonen, Laurent; Aydin, Selda; Robledo, Mercedes; Vikkula, Miikka; de Krijger, Ronald R; Dinjens, Winand N M; ... (2018). Expression of Contactin 4 is associated with malignant behavior in pheochromocytomas and paragangliomas. The Journal of clinical endocrinology and metabolism, 103(1), pp. 46-55. The Endocrine Society 10.1210/jc.2017-01314

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Context Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine, usually benign tumors. Currently, the only reliable criterion of malignancy is the presence of metastases. Objective The aim was to identify genes associated with malignancy in PPGL. Design Transcriptomic profiling was performed on 40 benign and 11 malignant PPGL. Genes showing a significantly different expression between benign and malignant PPGL with a ratio ≥ 4 were confirmed, and subsequently tested in an independent series by qRT-PCR. Immunohistochemistry was performed for the validated genes on 109 benign and 32 malignant PPGL. Finally, functional assays were performed with hPheo1 cells. Setting Department of Pathology of the Erasmus MC University Medical Center Rotterdam; Human Molecular Genetics laboratory of the de Duve Institute, University of Louvain. Patients PPGL samples from 179 patients, diagnosed between 1972 and 2015 were included. Main outcome measures Associations between gene expression and malignancy were tested using supervised clustering approaches. Results Ten differentially expressed genes were selected based on mRNA expression array data. Contactin 4 was overexpressed in malignant vs. benign tumors (4.62-fold, FDR: 0.001). Overexpression at the mRNA level was confirmed using qRT-PCR (2.90-fold, p=0.02; validation set: 4.26-fold, p=0.005). Consistent findings were obtained in the TCGA cohort (2.7-fold, FDR: 0.02). Furthermore, Contactin 4 protein was more frequently expressed in malignant than in benign PPGL by immunohistochemistry (58% vs. 17%, p=0.002). Finally, survival after 7 days of culture under starvation conditions was significantly enhanced in hPheo1 cells transfected with CNTN4 cDNA. Conclusion CNTN4 expression is consistently associated with malignant behavior in PPGL.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Perren, Aurel


500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health




The Endocrine Society




Aurel Perren

Date Deposited:

16 Oct 2017 16:12

Last Modified:

11 Jan 2018 01:31

Publisher DOI:


PubMed ID:





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