DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer

Anne Jouinot; Guillaume Assie; Rossella Libe; Martin Fassnacht; Thomas Papathomas; Olivia Barreau; Bruno De La Villeon; Simon Faillot; Nadim Hamzaoui; Mario Neou; Karine Perlemoine; Fernande Rene-Corail; Stephanie Rodriguez; Mathilde Sibony; Frederique Tissier; Bertrand Dousset; Silviu Sbiera; Cristina Ronchi; Matthias Kroiss; Esther Korpershoek; Ronald De Krijger; Jens Waldmann; Detlef K. Bartsch; Marcus Quinkler; Magalie Haissaguerre; Antoine Tabarin; Olivier Chabre; Nathalie Sturm; Michaela Luconi; Franco Mantero; Massimo Mannelli; Regis Cohen; Veronique Kerlan; Philippe Touraine; Gaelle Barrande; Lionel Groussin; Xavier Bertagna; Eric Baudin; Laurence Amar; Felix Beuschlein; Eric Clauser; Joel Coste; Jerome Bertherat

doi:10.1210/jc.2016-3205

DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer

Anne Jouinot, Guillaume Assie, Rossella Libe, Martin Fassnacht, Thomas Papathomas, Olivia Barreau, Bruno De La Villeon, Simon Faillot, Nadim Hamzaoui, Mario Neou, Karine Perlemoine, Fernande Rene-Corail, Stephanie Rodriguez, Mathilde Sibony, Frederique Tissier, Bertrand Dousset, Silviu Sbiera, Cristina Ronchi, Matthias Kroiss, Esther KorpershoekRonald De Krijger, Jens Waldmann, Detlef K. Bartsch, Marcus Quinkler, Magalie Haissaguerre, Antoine Tabarin, Olivier Chabre, Nathalie Sturm, Michaela Luconi, Franco Mantero, Massimo Mannelli, Regis Cohen, Veronique Kerlan, Philippe Touraine, Gaelle Barrande, Lionel Groussin, Xavier Bertagna, Eric Baudin, Laurence Amar, Felix Beuschlein, Eric Clauser, Joel Coste, Jerome Bertherat^*

^*Corresponding author for this work

Metabolism and Systems Research

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

39 Citations (Scopus)

Abstract

Context: Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival. Objective: The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort. Design: Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Setting: MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers. Patients: The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors). Main Outcome Measures: DFS and OS. Results: In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P , 0.0001) and OS (P , 0.0001). Methylation, Ki67, and ENSAT stage were combined inmultivariatemodels. For DFS,methylation (P = 0.0005) and stage (P,0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P , 0.0001), and Ki67 (P = 0.024) were independent prognostic factors. Conclusions: Tumor DNA methylation emerges as an independent prognostic factor in ACC. MSMLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.

Original language	English
Pages (from-to)	923-932
Number of pages	10
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	102
Issue number	3
Early online date	14 Dec 2016
DOIs	https://doi.org/10.1210/jc.2016-3205
Publication status	Published - 1 Mar 2017

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Biochemistry
Endocrinology
Clinical Biochemistry
Biochemistry, medical

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1210/jc.2016-3205Licence: None: All rights reserved

https://academic.oup.com/jcem/article/102/3/923/3061915Licence: None: All rights reserved

Cite this

Jouinot, A., Assie, G., Libe, R., Fassnacht, M., Papathomas, T., Barreau, O., De La Villeon, B., Faillot, S., Hamzaoui, N., Neou, M., Perlemoine, K., Rene-Corail, F., Rodriguez, S., Sibony, M., Tissier, F., Dousset, B., Sbiera, S., Ronchi, C., Kroiss, M., ... Bertherat, J. (2017). DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer. Journal of Clinical Endocrinology and Metabolism, 102(3), 923-932. https://doi.org/10.1210/jc.2016-3205

@article{2fab3f7145db4fdc9b0bbe13b39e33ae,

title = "DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer",

abstract = "Context: Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival. Objective: The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort. Design: Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Setting: MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers. Patients: The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors). Main Outcome Measures: DFS and OS. Results: In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P , 0.0001) and OS (P , 0.0001). Methylation, Ki67, and ENSAT stage were combined inmultivariatemodels. For DFS,methylation (P = 0.0005) and stage (P,0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P , 0.0001), and Ki67 (P = 0.024) were independent prognostic factors. Conclusions: Tumor DNA methylation emerges as an independent prognostic factor in ACC. MSMLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.",

author = "Anne Jouinot and Guillaume Assie and Rossella Libe and Martin Fassnacht and Thomas Papathomas and Olivia Barreau and {De La Villeon}, Bruno and Simon Faillot and Nadim Hamzaoui and Mario Neou and Karine Perlemoine and Fernande Rene-Corail and Stephanie Rodriguez and Mathilde Sibony and Frederique Tissier and Bertrand Dousset and Silviu Sbiera and Cristina Ronchi and Matthias Kroiss and Esther Korpershoek and {De Krijger}, Ronald and Jens Waldmann and Bartsch, {Detlef K.} and Marcus Quinkler and Magalie Haissaguerre and Antoine Tabarin and Olivier Chabre and Nathalie Sturm and Michaela Luconi and Franco Mantero and Massimo Mannelli and Regis Cohen and Veronique Kerlan and Philippe Touraine and Gaelle Barrande and Lionel Groussin and Xavier Bertagna and Eric Baudin and Laurence Amar and Felix Beuschlein and Eric Clauser and Joel Coste and Jerome Bertherat",

year = "2017",

month = mar,

day = "1",

doi = "10.1210/jc.2016-3205",

language = "English",

volume = "102",

pages = "923--932",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "3",

}

Jouinot, A, Assie, G, Libe, R, Fassnacht, M, Papathomas, T, Barreau, O, De La Villeon, B, Faillot, S, Hamzaoui, N, Neou, M, Perlemoine, K, Rene-Corail, F, Rodriguez, S, Sibony, M, Tissier, F, Dousset, B, Sbiera, S, Ronchi, C, Kroiss, M, Korpershoek, E, De Krijger, R, Waldmann, J, Bartsch, DK, Quinkler, M, Haissaguerre, M, Tabarin, A, Chabre, O, Sturm, N, Luconi, M, Mantero, F, Mannelli, M, Cohen, R, Kerlan, V, Touraine, P, Barrande, G, Groussin, L, Bertagna, X, Baudin, E, Amar, L, Beuschlein, F, Clauser, E, Coste, J & Bertherat, J 2017, 'DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer', Journal of Clinical Endocrinology and Metabolism, vol. 102, no. 3, pp. 923-932. https://doi.org/10.1210/jc.2016-3205

TY - JOUR

T1 - DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer

AU - Jouinot, Anne

AU - Assie, Guillaume

AU - Libe, Rossella

AU - Fassnacht, Martin

AU - Papathomas, Thomas

AU - Barreau, Olivia

AU - De La Villeon, Bruno

AU - Faillot, Simon

AU - Hamzaoui, Nadim

AU - Neou, Mario

AU - Perlemoine, Karine

AU - Rene-Corail, Fernande

AU - Rodriguez, Stephanie

AU - Sibony, Mathilde

AU - Tissier, Frederique

AU - Dousset, Bertrand

AU - Sbiera, Silviu

AU - Ronchi, Cristina

AU - Kroiss, Matthias

AU - Korpershoek, Esther

AU - De Krijger, Ronald

AU - Waldmann, Jens

AU - Bartsch, Detlef K.

AU - Quinkler, Marcus

AU - Haissaguerre, Magalie

AU - Tabarin, Antoine

AU - Chabre, Olivier

AU - Sturm, Nathalie

AU - Luconi, Michaela

AU - Mantero, Franco

AU - Mannelli, Massimo

AU - Cohen, Regis

AU - Kerlan, Veronique

AU - Touraine, Philippe

AU - Barrande, Gaelle

AU - Groussin, Lionel

AU - Bertagna, Xavier

AU - Baudin, Eric

AU - Amar, Laurence

AU - Beuschlein, Felix

AU - Clauser, Eric

AU - Coste, Joel

AU - Bertherat, Jerome

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Context: Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival. Objective: The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort. Design: Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Setting: MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers. Patients: The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors). Main Outcome Measures: DFS and OS. Results: In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P , 0.0001) and OS (P , 0.0001). Methylation, Ki67, and ENSAT stage were combined inmultivariatemodels. For DFS,methylation (P = 0.0005) and stage (P,0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P , 0.0001), and Ki67 (P = 0.024) were independent prognostic factors. Conclusions: Tumor DNA methylation emerges as an independent prognostic factor in ACC. MSMLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.

AB - Context: Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival. Objective: The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort. Design: Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Setting: MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers. Patients: The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors). Main Outcome Measures: DFS and OS. Results: In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P , 0.0001) and OS (P , 0.0001). Methylation, Ki67, and ENSAT stage were combined inmultivariatemodels. For DFS,methylation (P = 0.0005) and stage (P,0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P , 0.0001), and Ki67 (P = 0.024) were independent prognostic factors. Conclusions: Tumor DNA methylation emerges as an independent prognostic factor in ACC. MSMLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.

UR - http://www.scopus.com/inward/record.url?scp=85015167007&partnerID=8YFLogxK

U2 - 10.1210/jc.2016-3205

DO - 10.1210/jc.2016-3205

M3 - Article

AN - SCOPUS:85015167007

SN - 0021-972X

VL - 102

SP - 923

EP - 932

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 3

ER -

DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Fingerprint

Cite this