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

doi:10.1186/s40478-022-01344-5

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

Neurology

Research output: Contribution to journal › Article › Academic › peer-review

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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 language	English
Article number	39
Journal	Acta neuropathologica communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1186/s40478-022-01344-5
Publication status	Published - 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:
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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DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome—including in elderly patientsFinal published version, 3.32 MBLicence: CC BY

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Bady, P., Marosi, C., Weller, M., Grønberg, B. H., Schultz, H., Taphoorn, M. J. B., Gijtenbeek, J. M. M., van den Bent, M. J., von Deimling, A., Stupp, R., Malmström, A., & Hegi, M. E. (2022). DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome—including in elderly patients. Acta neuropathologica communications, 10(1), Article 39. https://doi.org/10.1186/s40478-022-01344-5

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

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{\textquoteright} 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.",

author = "Pierre Bady and Christine Marosi and Michael Weller and Gr{\o}nberg, {Bj{\o}rn H.} and Henrik Schultz and Taphoorn, {Martin J.B.} and Gijtenbeek, {Johanna M.M.} and {van den Bent}, {Martin J.} and {von Deimling}, Andreas and Roger Stupp and Annika Malmstr{\"o}m and Hegi, {Monika E.}",

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: 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: {\textcopyright} 2022, The Author(s).",

year = "2022",

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doi = "10.1186/s40478-022-01344-5",

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Bady, P, Marosi, C, Weller, M, Grønberg, BH, Schultz, H, Taphoorn, MJB, Gijtenbeek, JMM, van den Bent, MJ, von Deimling, A, Stupp, R, Malmström, A & Hegi, ME 2022, 'DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome—including in elderly patients', Acta neuropathologica communications, vol. 10, no. 1, 39. https://doi.org/10.1186/s40478-022-01344-5

TY - JOUR

T1 - DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome—including in elderly patients

AU - Bady, Pierre

AU - Marosi, Christine

AU - Weller, Michael

AU - Grønberg, Bjørn H.

AU - Schultz, Henrik

AU - Taphoorn, Martin J.B.

AU - Gijtenbeek, Johanna M.M.

AU - van den Bent, Martin J.

AU - von Deimling, Andreas

AU - Stupp, Roger

AU - Malmström, Annika

AU - Hegi, Monika E.

N1 - 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: 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).

PY - 2022/3/24

Y1 - 2022/3/24

N2 - 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.

AB - 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.

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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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