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.

Interest & Impact

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Citations

5 Citations in Web of Science ®
6 Citations in Scopus

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