The Journal of clinical endocrinology and metabolism · 2018
Expression of Contactin 4 Is Associated With Malignant Behavior in Pheochromocytomas and Paragangliomas.
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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, Ghayee Hans K, Shay Jerry W, 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, Persu Alexandre, Korpershoek Esther
Аннотация
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.
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.