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DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome - including in elderly patients
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- Bady, Pierre (författare)
- Swiss Inst Bioinformat SIB, Switzerland; Lausanne Univ Hop, Switzerland; Univ Lausanne, Switzerland
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- Marosi, Christine (författare)
- Univ Vienna, Austria
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- Weller, Michael (författare)
- Univ Hosp, Switzerland; Univ Zurich, Switzerland
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- Gronberg, Bjorn H. (författare)
- Norwegian Univ Sci & Technol, Norway; St Olays Hosp, Norway
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- Schultz, Henrik (författare)
- Aarhus Univ Hosp, Denmark
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- Taphoorn, Martin J. B. (författare)
- Leiden Univ, Netherlands; Haaglanden Med Ctr, Netherlands
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- Gijtenbeek, Johanna M. M. (författare)
- Radboud Univ Nijmegen, Netherlands
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- van den Bent, Martin J. (författare)
- Erasmus MC, Netherlands
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- von Deimling, Andreas (författare)
- Heidelberg Univ, Germany; German Canc Ctr DKFZ, Germany
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- Stupp, Roger (författare)
- Northwestern Med, IL USA; Northwestern Med, IL USA; Northwestern Univ, IL 60611 USA
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- Malmström, Annika (författare)
- Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten,Region Östergötland, Närvårdskliniken
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- Hegi, Monika E. (författare)
- Lausanne Univ Hop, Switzerland; Univ Lausanne, Switzerland; Univ Lausanne UNIL, Switzerland; Swiss Canc Ctr Leman SCCL, Switzerland
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(creator_code:org_t)
- 2022-03-24
- Engelska.
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Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 10:1
- Relaterad länk:
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https://liu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- DNA methylation age acceleration; Glioblastoma IDHwt; Survival; Methylome; Age
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
- Av författaren/redakt...
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Bady, Pierre
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Marosi, Christin ...
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Weller, Michael
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Gronberg, Bjorn ...
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Schultz, Henrik
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Taphoorn, Martin ...
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visa fler...
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Gijtenbeek, Joha ...
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van den Bent, Ma ...
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von Deimling, An ...
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Stupp, Roger
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Malmström, Annik ...
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Hegi, Monika E.
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Cancer och onkol ...
- Artiklar i publikationen
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Acta neuropathol ...
- Av lärosätet
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Linköpings universitet