Titre
DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome-including in elderly patients.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Bady, P.
Auteure/Auteur
Marosi, C.
Auteure/Auteur
Weller, M.
Auteure/Auteur
Grønberg, B.H.
Auteure/Auteur
Schultz, H.
Auteure/Auteur
Taphoorn, MJB
Auteure/Auteur
Gijtenbeek, JMM
Auteure/Auteur
van den Bent, M.J.
Auteure/Auteur
von Deimling, A.
Auteure/Auteur
Stupp, R.
Auteure/Auteur
Malmström, A.
Auteure/Auteur
Hegi, M.E.
Auteure/Auteur
Liens vers les personnes
ISSN
2051-5960
Statut éditorial
Publié
Date de publication
2022-03-24
Volume
10
Numéro
1
Première page
39
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
Résumé
Elderly patients represent a growing proportion of individuals with glioblastoma, who however, are often excluded from clinical trials owing to poor expected prognosis. We aimed at identifying age-related molecular differences that would justify and guide distinct treatment decisions in elderly glioblastoma patients. The combined DNA methylome (450 k) of four IDH wild-type glioblastoma datasets, comprising two clinical trial cohorts, was interrogated for differences based on the patients' age, DNA methylation (DNAm) age acceleration (DNAm age "Horvath-clock" minus patient age), DNA methylation-based tumor classification (Heidelberg), entropy, and functional methylation of DNA damage response (DDR) genes. Age dependent methylation included 19 CpGs (p-value ≤ 0.1, Bonferroni corrected), comprising a CpG located in the ELOVL2 gene that is part of a 13-gene forensic age predictor. Most of the age related CpGs (n = 16) were also associated with age acceleration that itself was associated with a large number of CpGs (n = 50,551). Over 70% age acceleration-associated CpGs (n = 36,348) overlapped with those associated with the DNA methylation based tumor classification (n = 170,759). Gene set enrichment analysis identified associated pathways, providing insights into the biology of DNAm age acceleration and respective commonalities with glioblastoma classification. Functional methylation of several DDR genes, defined as correlation of methylation with gene expression (r ≤ -0.3), was associated with age acceleration (n = 8), tumor classification (n = 12), or both (n = 4), the latter including MGMT. DNAm age acceleration was significantly associated with better outcome in both clinical trial cohorts, whereof one comprised only elderly patients. Multivariate analysis included treatment (RT, RT/TMZ→TMZ; TMZ, RT), MGMT promoter methylation status, and interaction with treatment. In conclusion, DNA methylation features of age acceleration are an integrative part of the methylation-based tumor classification (RTK I, RTK II, MES), while patient age seems hardly reflected in the glioblastoma DNA methylome. We found no molecular evidence justifying other treatments in elderly patients, not owing to frailty or co-morbidities.
PID Serval
serval:BIB_3D6A92122001
PMID
Open Access
Oui
Date de création
2022-02-18T15:27:44.058Z
Date de création dans IRIS
2025-05-20T14:03:10Z
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Nom
Bady_etal_2022_ANEC_AgeAcc-GBM_97b7ef23-c14a-4bb4-afae-8ec0c0a1fc63.pdf
Version du manuscrit
preprint
Licence
https://creativecommons.org/licenses/by/4.0
Taille
3.32 MB
Format
Adobe PDF
PID Serval
serval:BIB_3D6A92122001.P001
URN
urn:nbn:ch:serval-BIB_3D6A921220010
Somme de contrôle
(MD5):b38bc4c33a4f2bb0036946bc566c8bce