The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033.

Détails

Ressource 1Télécharger: Bady_et_al-2018-Acta_Neuropathologica.pdf (3924.77 [Ko])
Etat: Serval
Version: de l'auteur
Document(s) secondaire(s)
Télécharger: Bady_et_al-2018-Acta_Neuropathologica.sup-1.pdf (962.25 [Ko])
Etat: Serval
Version: Supplementary document
ID Serval
serval:BIB_424F6D3B26FB
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033.
Périodique
Acta neuropathologica
Auteur(s)
Bady P., Kurscheid S., Delorenzi M., Gorlia T., van den Bent M.J., Hoang-Xuan K., Vauléon É., Gijtenbeek A., Enting R., Thiessen B., Chinot O., Dhermain F., Brandes A.A., Reijneveld J.C., Marosi C., Taphoorn MJB, Wick W., von Deimling A., French P., Stupp R., Baumert B.G., Hegi M.E.
ISSN
1432-0533 (Electronic)
ISSN-L
0001-6322
Statut éditorial
Publié
Date de publication
04/2018
Peer-reviewed
Oui
Volume
135
Numéro
4
Pages
601-615
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes. We first identified 62 functionally relevant CpG sites located in the promoters of 24 DDR genes, using the LGG data from The Cancer Genome Atlas. Then we tested their association with outcome [progression-free survival (PFS)] depending on treatment in 120 LGG patients of EORTC 22033, whose tumors were mutant for isocitrate dehydrogenase 1 or 2 (IDHmt), the molecular hallmark of LGG. The results suggested that seven CpGs of four DDR genes may be predictive for longer PFS in one of the treatment arms that comprised MGMT, MLH3, RAD21, and SMC4. Most interestingly, the two CpGs identified for MGMT are the same, previously selected for the MGMT-STP27 score that is used to determine the methylation status of the MGMT gene. This score was higher in the LGG with 1p/19q codeletion, in this and other independent LGG datasets. It was predictive for PFS in the TMZ, but not in the RT arm of EORTC 22033. The results support the hypothesis that a high score predicts benefit from TMZ treatment for patients with IDHmt LGG, regardless of the 1p/19q status. This MGMT methylation score may identify patients who benefit from first-line treatment with TMZ, to defer RT for long-term preservation of cognitive function and quality of life.

Mots-clé
DDR genes, DNA methylation, Low-grade glioma, MGMT-STP27, Randomized trial, TMZ
Pubmed
Web of science
Open Access
Oui
Création de la notice
01/02/2018 21:40
Dernière modification de la notice
08/05/2019 17:43
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