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000163689 1001_ $$00000-0003-3288-2047$$aDodgshun, Andrew J$$b0
000163689 245__ $$aGermline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns.
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000163689 520__ $$aReplication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled 'Wild type-C' or 'Paediatric RTK 1'. Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.
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000163689 7001_ $$aFukuoka, Kohei$$b1
000163689 7001_ $$aEdwards, Melissa$$b2
000163689 7001_ $$aBianchi, Vanessa J$$b3
000163689 7001_ $$aDas, Anirban$$b4
000163689 7001_ $$aSexton-Oates, Alexandra$$b5
000163689 7001_ $$aLarouche, Valérie$$b6
000163689 7001_ $$aVanan, Magimairajan I$$b7
000163689 7001_ $$aLindhorst, Scott$$b8
000163689 7001_ $$aYalon, Michal$$b9
000163689 7001_ $$aMason, Gary$$b10
000163689 7001_ $$aCrooks, Bruce$$b11
000163689 7001_ $$aConstantini, Shlomi$$b12
000163689 7001_ $$aMassimino, Maura$$b13
000163689 7001_ $$aChiaravalli, Stefano$$b14
000163689 7001_ $$aRamdas, Jagadeesh$$b15
000163689 7001_ $$aMason, Warren$$b16
000163689 7001_ $$aAshraf, Shamvil$$b17
000163689 7001_ $$aFarah, Roula$$b18
000163689 7001_ $$aVan Damme, An$$b19
000163689 7001_ $$aOpocher, Enrico$$b20
000163689 7001_ $$aHamid, Syed Ahmer$$b21
000163689 7001_ $$aZiegler, David S$$b22
000163689 7001_ $$aSamuel, David$$b23
000163689 7001_ $$aCole, Kristina A$$b24
000163689 7001_ $$aTomboc, Patrick$$b25
000163689 7001_ $$aStearns, Duncan$$b26
000163689 7001_ $$aThomas, Gregory A$$b27
000163689 7001_ $$aLossos, Alexander$$b28
000163689 7001_ $$aSullivan, Michael$$b29
000163689 7001_ $$aHansford, Jordan R$$b30
000163689 7001_ $$aMackay, Alan$$b31
000163689 7001_ $$aJones, Chris$$b32
000163689 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David T W$$b33$$udkfz
000163689 7001_ $$aRamaswamy, Vijay$$b34
000163689 7001_ $$aHawkins, Cynthia$$b35
000163689 7001_ $$aBouffet, Eric$$b36
000163689 7001_ $$aTabori, Uri$$b37
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