Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns
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ORIGINAL PAPER
Germline‑driven replication repair‑deficient high‑grade gliomas exhibit unique hypomethylation patterns Andrew J. Dodgshun1 · Kohei Fukuoka2 · Melissa Edwards2 · Vanessa J. Bianchi3 · Anirban Das2 · Alexandra Sexton‑Oates4 · Valérie Larouche5 · Magimairajan I. Vanan6 · Scott Lindhorst7 · Michal Yalon8 · Gary Mason9 · Bruce Crooks10 · Shlomi Constantini11 · Maura Massimino12 · Stefano Chiaravalli12 · Jagadeesh Ramdas13 · Warren Mason14 · Shamvil Ashraf15 · Roula Farah16 · An Van Damme17 · Enrico Opocher18 · Syed Ahmer Hamid15 · David S. Ziegler19 · David Samuel20 · Kristina A. Cole21 · Patrick Tomboc22 · Duncan Stearns23 · Gregory A. Thomas24 · Alexander Lossos25 · Michael Sullivan26 · Jordan R. Hansford26 · Alan Mackay27 · Chris Jones27 · David T. W. Jones28 · Vijay Ramaswamy2 · Cynthia Hawkins2 · Eric Bouffet2 · Uri Tabori2 Received: 1 June 2020 / Revised: 21 July 2020 / Accepted: 3 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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. Keywords Glioma · Glioblastoma · DNA repair · DNA methylation · DNA mismatch repair
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00401-020-02209-8) contains supplementary material, which is available to authorized users. * Andrew J.
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