1. Expression of Contactin 4 Is Associated With Malignant Behavior in Pheochromocytomas and Paragangliomas.
- Author
-
Evenepoel L, van Nederveen FH, Oudijk L, Papathomas TG, Restuccia DF, Belt EJT, de Herder WW, Feelders RA, Franssen GJH, Hamoir M, Maiter D, Ghayee HK, Shay JW, Perren A, Timmers HJLM, van Eeden S, Vroonen L, Aydin S, Robledo M, Vikkula M, de Krijger RR, Dinjens WNM, Persu A, and Korpershoek E
- Subjects
- Adrenal Gland Neoplasms genetics, Adrenal Gland Neoplasms metabolism, Biomarkers, Tumor genetics, Contactins genetics, Gene Expression Profiling, Humans, Paraganglioma genetics, Paraganglioma metabolism, Pheochromocytoma genetics, Pheochromocytoma metabolism, Prognosis, RNA, Messenger genetics, Adrenal Gland Neoplasms diagnosis, Biomarkers, Tumor metabolism, Contactins metabolism, Paraganglioma diagnosis, Pheochromocytoma diagnosis, RNA, Messenger metabolism
- Abstract
Context: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine, usually benign, tumors. Currently, the only reliable criterion of malignancy is the presence of metastases., Objective: The aim of this study was to identify genes associated with malignancy in PPGLs., Design: Transcriptomic profiling was performed on 40 benign and 11 malignant PPGLs. Genes showing a significantly different expression between benign and malignant PPGLs with a ratio ≥4 were confirmed and tested in an independent series by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed for the validated genes on 109 benign and 32 malignant PPGLs. Functional assays were performed with hPheo1 cells., Setting: This study was conducted at the 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 messenger RNA (mRNA) expression array data. Contactin 4 (CNTN4) was overexpressed in malignant vs benign tumors [4.62-fold; false discovery rate (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 Cancer Genome Atlas cohort (2.7-fold; FDR, 0.02). CNTN4 protein was more frequently expressed in malignant than in benign PPGLs by immunohistochemistry (58% vs 17%; P = 0.002). Survival after 7 days of culture under starvation conditions was significantly enhanced in hPheo1 cells transfected with CNTN4 complementary DNA., Conclusion: CNTN4 expression is consistently associated with malignant behavior in PPGLs., (Copyright © 2017 Endocrine Society)
- Published
- 2018
- Full Text
- View/download PDF