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.
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Data is available at the Gene Expression Omnibus (GEO), accession number GSE157397.
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Acknowledgements
Research supported by a Stand Up to Cancer- Bristol-Meyers Squibb Catalyst Research Grant (Grant Number: SU2C-AACR-CT07-17). This research grant is administered by the American Association for Cancer Research, the scientific partner of SU2C. This work was supported by the Canada-Israel Health Research initiative, jointly funded by the Canadian Institutes of Health Research, the Israel Science Foundation, the International Development Research Centre, Canada, and the Azrieli Foundation. We also acknowledge financial support from a Canadian Health Institutes Research grant, Meagan’s Walk (MW-2014-10), LivWise, BRAINchild, Tokyo Children's Cancer Study Group (TCCSG) scholarship of the Gold Ribbons Network of Japan, Restracomp Scholarship, and the Royal Children’s Hospital Foundation.
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AD, JRH, MS, AS-O, and UT were involved in study conception. AD, KF, ME, VB, DTWJ, VR, and UT were involved in data processing and interpretation. AD and UT wrote the manuscript. All authors were involved in the acquisition of data, either in the consent of patients, procurement of samples, acquisition of molecular data, or provision of comparison data sets. All authors contributed to editing the manuscript for accuracy and clarity and all authors have approved the final manuscript.
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Dodgshun, A.J., Fukuoka, K., Edwards, M. et al. Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns. Acta Neuropathol 140, 765–776 (2020). https://doi.org/10.1007/s00401-020-02209-8
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DOI: https://doi.org/10.1007/s00401-020-02209-8