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
N1 - Publisher Copyright:
Copyright © 2017 by the Endocrine Society.
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
C2 - 27967600
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 -