Expression of Contactin 4 Is Associated With Malignant Behavior in Pheochromocytomas and Paragangliomas

Lucie Evenepoel; Francien H van Nederveen; Lindsey Oudijk; Thomas Papathomas; David F Restuccia; Eric J T Belt; Wouter W de Herder; R A Feelders; Gaston J H Franssen; Marc Hamoir; D Maiter; Hans K Ghayee; Jerry W Shay; Aurel Perren; Henri J Timmers; Susanne van Eeden; Laurent Vroonen; Selda Aydin; Mercedes Robledo; Miikka Vikkula; Ronald De Krijger; WNM Dinjens; Alexandre Persu; Esther Korpershoek

doi:10.1210/jc.2017-01314

Expression of Contactin 4 Is Associated With Malignant Behavior in Pheochromocytomas and Paragangliomas

Lucie Evenepoel, Francien H van Nederveen, Lindsey Oudijk, Thomas Papathomas, David F Restuccia, Eric J T Belt, Wouter W de Herder, R A Feelders, Gaston J H Franssen, Marc Hamoir, D Maiter, Hans K Ghayee, Jerry W Shay, Aurel Perren, Henri J Timmers, Susanne van Eeden, Laurent Vroonen, Selda Aydin, Mercedes Robledo, Miikka VikkulaRonald De Krijger, WNM Dinjens, Alexandre Persu, Esther Korpershoek

Metabolism and Systems Research

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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.

Original language	English
Pages (from-to)	46-55
Number of pages	10
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	103
Issue number	1
Early online date	17 Aug 2017
DOIs	https://doi.org/10.1210/jc.2017-01314
Publication status	Published - 1 Jan 2018

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Evenepoel, L., van Nederveen, F. H., Oudijk, L., Papathomas, T., Restuccia, D. F., Belt, E. J. T., de Herder, W. W., Feelders, R. A., Franssen, G. J. H., Hamoir, M., Maiter, D., Ghayee, H. K., Shay, J. W., Perren, A., Timmers, H. J., van Eeden, S., Vroonen, L., Aydin, S., Robledo, M., ... Korpershoek, E. (2018). Expression of Contactin 4 Is Associated With Malignant Behavior in Pheochromocytomas and Paragangliomas. Journal of Clinical Endocrinology and Metabolism, 103(1), 46-55. https://doi.org/10.1210/jc.2017-01314

@article{6ff54e20fb99483da490ead9659aea3f,

title = "Expression of Contactin 4 Is Associated With Malignant Behavior in Pheochromocytomas and Paragangliomas",

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.",

author = "Lucie Evenepoel and {van Nederveen}, {Francien H} and Lindsey Oudijk and Thomas Papathomas and Restuccia, {David F} and Belt, {Eric J T} and {de Herder}, {Wouter W} and Feelders, {R A} and Franssen, {Gaston J H} and Marc Hamoir and D Maiter and Ghayee, {Hans K} and Shay, {Jerry W} and Aurel Perren and Timmers, {Henri J} and {van Eeden}, Susanne and Laurent Vroonen and Selda Aydin and Mercedes Robledo and Miikka Vikkula and {De Krijger}, Ronald and WNM Dinjens and Alexandre Persu and Esther Korpershoek",

year = "2018",

month = jan,

day = "1",

doi = "10.1210/jc.2017-01314",

language = "English",

volume = "103",

pages = "46--55",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "1",

}

Evenepoel, L, van Nederveen, FH, Oudijk, L, Papathomas, T, Restuccia, DF, Belt, EJT, de Herder, WW, Feelders, RA, Franssen, GJH, Hamoir, M, Maiter, D, Ghayee, HK, Shay, JW, Perren, A, Timmers, HJ, van Eeden, S, Vroonen, L, Aydin, S, Robledo, M, Vikkula, M, De Krijger, R, Dinjens, WNM, Persu, A & Korpershoek, E 2018, 'Expression of Contactin 4 Is Associated With Malignant Behavior in Pheochromocytomas and Paragangliomas', Journal of Clinical Endocrinology and Metabolism, vol. 103, no. 1, pp. 46-55. https://doi.org/10.1210/jc.2017-01314

TY - JOUR

T1 - Expression of Contactin 4 Is Associated With Malignant Behavior in Pheochromocytomas and Paragangliomas

AU - Evenepoel, Lucie

AU - van Nederveen, Francien H

AU - Oudijk, Lindsey

AU - Papathomas, Thomas

AU - Restuccia, David F

AU - Belt, Eric J T

AU - de Herder, Wouter W

AU - Feelders, R A

AU - Franssen, Gaston J H

AU - Hamoir, Marc

AU - Maiter, D

AU - Ghayee, Hans K

AU - Shay, Jerry W

AU - Perren, Aurel

AU - Timmers, Henri J

AU - van Eeden, Susanne

AU - Vroonen, Laurent

AU - Aydin, Selda

AU - Robledo, Mercedes

AU - Vikkula, Miikka

AU - De Krijger, Ronald

AU - Dinjens, WNM

AU - Persu, Alexandre

AU - Korpershoek, Esther

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

U2 - 10.1210/jc.2017-01314

DO - 10.1210/jc.2017-01314

M3 - Article

SN - 0021-972X

VL - 103

SP - 46

EP - 55

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 1

ER -

Expression of Contactin 4 Is Associated With Malignant Behavior in Pheochromocytomas and Paragangliomas

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