TY  - JOUR
AU  - Dodgshun, Andrew J
AU  - Fukuoka, Kohei
AU  - Edwards, Melissa
AU  - Bianchi, Vanessa J
AU  - Das, Anirban
AU  - Sexton-Oates, Alexandra
AU  - Larouche, Valérie
AU  - Vanan, Magimairajan I
AU  - Lindhorst, Scott
AU  - Yalon, Michal
AU  - Mason, Gary
AU  - Crooks, Bruce
AU  - Constantini, Shlomi
AU  - Massimino, Maura
AU  - Chiaravalli, Stefano
AU  - Ramdas, Jagadeesh
AU  - Mason, Warren
AU  - Ashraf, Shamvil
AU  - Farah, Roula
AU  - Van Damme, An
AU  - Opocher, Enrico
AU  - Hamid, Syed Ahmer
AU  - Ziegler, David S
AU  - Samuel, David
AU  - Cole, Kristina A
AU  - Tomboc, Patrick
AU  - Stearns, Duncan
AU  - Thomas, Gregory A
AU  - Lossos, Alexander
AU  - Sullivan, Michael
AU  - Hansford, Jordan R
AU  - Mackay, Alan
AU  - Jones, Chris
AU  - Jones, David T W
AU  - Ramaswamy, Vijay
AU  - Hawkins, Cynthia
AU  - Bouffet, Eric
AU  - Tabori, Uri
TI  - Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns.
JO  - Acta neuropathologica
VL  - 140
IS  - 5
SN  - 1432-0533
CY  - Heidelberg
PB  - Springer
M1  - DKFZ-2020-01965
SP  - 765-776
PY  - 2020
N1  - 2020 Nov;140(5):765-776
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32895736
DO  - DOI:10.1007/s00401-020-02209-8
UR  - https://inrepo02.dkfz.de/record/163689
ER  -