DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome—including in elderly patients

Pierre Bady, Christine Marosi, Michael Weller, Bjørn H. Grønberg, Henrik Schultz, Martin J.B. Taphoorn, Johanna M.M. Gijtenbeek, Martin J. van den Bent, Andreas von Deimling, Roger Stupp, Annika Malmström, Monika E. Hegi*

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Article number39
JournalActa neuropathologica communications
Volume10
Issue number1
DOIs
Publication statusPublished - 24 Mar 2022

Bibliographical note

Funding Information:
We thank the patients and their families for their support and participation, and the treating clinical centers for collaboration. The results published here are in part based upon data generated by The Cancer TCGA Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions WHO constitute the TCGA research network can be found at “http://cancergenome.nih.gov ”. The dbGaP accession number to the specific version of the TCGA data set is phs000178.v8.p7.

Funding Information:
P.B.: None. C.M.: None. M.W.: reports grants and personal fees from Apogenix, grants and personal fees from Merck (EMD), grants from Quercis, grants and personal fees from Adastra, personal fees from BMS, Medac, Merck Sharp & Dohme, Nerviano, Novartis, Orbus, Philogen, and y-Mabs. B.H.G.: None. H.S.: None. M.J.B.T.: None. J.M.M.G.: None. M.J.vdB.: reports consulting fees from Abbvie, Celgene, Agios, Boehringer Ingelheim, Bayer, Carthera, Genenta, Nerviano, Boston pharmaceuticals and research funding from Abbvie. A.v.D.: reports a pending patent: DNA methylation-based method for classifying tumor species (EP16710700.2). R.S.: reports consulting for CarThera; Celularity; CranioVation/Alpheus; Hemispherian; Insightec; GT Medical Technologies; Northwest Biotherapeutics; TriAct. A.M.: None. M.E.H.: reports consulting fees from Hemispherian; NOXXON.

Funding Information:
The study was funded by the Swiss National Science Foundation (SNF-3103–163297, SNF-3103–182821), and the Swiss Cancer Research foundation (KFS-4461–02-2018).

Publisher Copyright:
© 2022, The Author(s).

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