Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns

Andrew J. Dodgshun*, Kohei Fukuoka, Melissa Edwards, Vanessa J. Bianchi, Anirban Das, Alexandra Sexton-Oates, Valérie Larouche, Magimairajan I. Vanan, Scott Lindhorst, Michal Yalon, Gary Mason, Bruce Crooks, Shlomi Constantini, Maura Massimino, Stefano Chiaravalli, Jagadeesh Ramdas, Warren Mason, Shamvil Ashraf, Roula Farah, An Van DammeEnrico Opocher, Syed Ahmer Hamid, David S. Ziegler, David Samuel, Kristina A. Cole, Patrick Tomboc, Duncan Stearns, Gregory A. Thomas, Alexander Lossos, Michael Sullivan, Jordan R. Hansford, Alan Mackay, Chris Jones, David T.W. Jones, Vijay Ramaswamy, Cynthia Hawkins, Eric Bouffet, Uri Tabori*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled “Wild type-C” or “Paediatric RTK 1”. Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.

Original languageEnglish
Pages (from-to)765-776
Number of pages12
JournalActa Neuropathologica
Issue number5
StatePublished - 1 Nov 2020
Externally publishedYes


FundersFunder number
Royal Children?s Hospital Foundation
American Association for Cancer Research
Royal Children's Hospital Foundation
Canadian Institutes of Health ResearchMW-2014-10
International Development Research Centre
Israel Science Foundation
Azrieli Foundation


    • DNA methylation
    • DNA mismatch repair
    • DNA repair
    • Glioblastoma
    • Glioma


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