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DNA methylation is an independent prognostic marker of survival in adrenocortical cancer

Anne Jouinot 1, 2, 3 Guillaume Assie 1, 2, 3 Rossella Libé 3, 1, 2 Martin Fassnacht 4 Thomas Papathomas Olivia Barreau 3, 1, 2 Bruno de la Villeon 3, 1, 2 Simon Faillot 3, 1, 2 Nadim Hamzaoui 3 Mario Neou 1, 3, 2 Karine Perlemoine 1, 3, 2 Fernande Rene-Corail 1, 3, 2 Stéphanie Rodriguez 1, 3, 2 Mathilde Sibony 1, 3, 2 Fréderique Tissier 1, 2, 3 Bertrand Dousset 3, 5 Silviu Sbiera 6 Cristina Ronchi 7 Matthias Kroiss Esther Korpershoek 8 Ronald de Krijger 9 Jens Waldmann Detlef Bartsch Marcus Quinkler Magalie Haissaguerre 10 Antoine Tabarin 10 Olivier Chabre 11 Nathalie Sturm 12 Michaela Luconi Franco Mantero Massimo Mannelli Regis Cohen 13 Véronique Kerlan 14, 15 Philippe Touraine 16 Gaelle Barrande 17 Lionel Groussin 1, 3, 2 Xavier Bertagna 1, 3, 2 Éric Baudin 18 Laurence Amar 19 Felix Beuschlein 6 Eric Clauser 20 Joël Coste 21 Jérôme Bertherat 1, 3, 2
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 in multivariate models. 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. MS-MLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.
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Submitted on : Tuesday, February 26, 2019 - 2:52:59 PM
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Anne Jouinot, Guillaume Assie, Rossella Libé, Martin Fassnacht, Thomas Papathomas, et al.. DNA methylation is an independent prognostic marker of survival in adrenocortical cancer. Journal of Clinical Endocrinology and Metabolism, Endocrine Society, 2016, pp.jc.2016-3205. ⟨10.1210/jc.2016-3205⟩. ⟨hal-02049555⟩



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