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 L. 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)
1
IC UM3 (UMR 8104 / U1016) -
Institut Cochin
2 UPD5 - Université Paris Descartes - Paris 5
3 Hôpital Cochin [AP-HP]
4 Department of Psychiatry
5 Chirurgie digestive, hépato-biliaire et endocrinienne [CHU Cochin]
6 Medizinische Klinik und Poliklinik IV
7 Comprehensive Cancer Center Mainfranken
8 Department of Pathology
9 Clinical Genetics
10 Département d'endocrinologie - Bordeaux 2
11 GHE - Groupement Hospitalier Lyon-Est
12 Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques
13 Department of Endocrinology and Diabetes Mellitus
14 CHRU - Endocrino - Service d'Endocrinologie
15 GETBO - Groupe d'Etude de la Thrombose de Bretagne Occidentale
16 CHU Pitié-Salpêtrière [AP-HP]
17 CHRO - Centre Hospitalier Régional d'Orléans
18 Médecine nucléaire
19 HEGP - Hôpital Européen Georges Pompidou [APHP]
20 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
21 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
2 UPD5 - Université Paris Descartes - Paris 5
3 Hôpital Cochin [AP-HP]
4 Department of Psychiatry
5 Chirurgie digestive, hépato-biliaire et endocrinienne [CHU Cochin]
6 Medizinische Klinik und Poliklinik IV
7 Comprehensive Cancer Center Mainfranken
8 Department of Pathology
9 Clinical Genetics
10 Département d'endocrinologie - Bordeaux 2
11 GHE - Groupement Hospitalier Lyon-Est
12 Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques
13 Department of Endocrinology and Diabetes Mellitus
14 CHRU - Endocrino - Service d'Endocrinologie
15 GETBO - Groupe d'Etude de la Thrombose de Bretagne Occidentale
16 CHU Pitié-Salpêtrière [AP-HP]
17 CHRO - Centre Hospitalier Régional d'Orléans
18 Médecine nucléaire
19 HEGP - Hôpital Européen Georges Pompidou [APHP]
20 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
21 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
Anne Jouinot
- Fonction : Auteur
- PersonId : 753239
- IdHAL : anne-jouinot
- ORCID : 0000-0002-7922-2065
Martin Fassnacht
- Fonction : Auteur
- PersonId : 763136
- ORCID : 0000-0001-6170-6398
Thomas Papathomas
- Fonction : Auteur
Mario Neou
- Fonction : Auteur
Mathilde Sibony
- Fonction : Auteur
- PersonId : 916770
Bertrand Dousset
- Fonction : Auteur
- PersonId : 776416
- ORCID : 0000-0003-2526-7345
- IdRef : 058941568
Matthias Kroiss
- Fonction : Auteur
- PersonId : 776414
- ORCID : 0000-0002-7628-3161
Jens Waldmann
- Fonction : Auteur
Detlef Bartsch
- Fonction : Auteur
Marcus Quinkler
- Fonction : Auteur
- PersonId : 776415
- ORCID : 0000-0003-4028-1671
Michaela Luconi
- Fonction : Auteur
Franco Mantero
- Fonction : Auteur
Massimo Mannelli
- Fonction : Auteur
Laurence Amar
- Fonction : Auteur
- PersonId : 759846
- ORCID : 0000-0003-3942-4276
- IdRef : 092993508
Felix Beuschlein
- Fonction : Auteur
- PersonId : 758956
- ORCID : 0000-0001-7826-3984
Résumé
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.