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 Damme; Enrico 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

doi:10.1007/s00401-020-02209-8

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

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

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.

Original language	English
Pages (from-to)	765-776
Number of pages	12
Journal	Acta Neuropathologica
Volume	140
Issue number	5
DOIs	https://doi.org/10.1007/s00401-020-02209-8
Publication status	Published - Nov 1 2020
Externally published	Yes

Bibliographical note

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

ASJC Scopus Subject Areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00401-020-02209-8

Cite this

Dodgshun, A. J., Fukuoka, K., Edwards, M., Bianchi, V. J., Das, A., Sexton-Oates, A., Larouche, V., Vanan, M. I., Lindhorst, S., Yalon, M., Mason, G., Crooks, B., Constantini, S., Massimino, M., Chiaravalli, S., Ramdas, J., Mason, W., Ashraf, S., Farah, R., ... Tabori, U. (2020). Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns. Acta Neuropathologica, 140(5), 765-776. https://doi.org/10.1007/s00401-020-02209-8

Dodgshun, AJ, Fukuoka, K, Edwards, M, Bianchi, VJ, Das, A, Sexton-Oates, A, Larouche, V, Vanan, MI, Lindhorst, S, Yalon, M, Mason, G, Crooks, B, Constantini, S, Massimino, M, Chiaravalli, S, Ramdas, J, Mason, W, Ashraf, S, Farah, R, Van Damme, A, Opocher, E, Hamid, SA, Ziegler, DS, Samuel, D, Cole, KA, Tomboc, P, Stearns, D, Thomas, GA, Lossos, A, Sullivan, M, Hansford, JR, Mackay, A, Jones, C, Jones, DTW, Ramaswamy, V, Hawkins, C, Bouffet, E & Tabori, U 2020, 'Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns', Acta Neuropathologica, vol. 140, no. 5, pp. 765-776. https://doi.org/10.1007/s00401-020-02209-8

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title = "Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns",

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.",

author = "Dodgshun, {Andrew J.} and Kohei Fukuoka and Melissa Edwards and Bianchi, {Vanessa J.} and Anirban Das and Alexandra Sexton-Oates and Val{\'e}rie Larouche and Vanan, {Magimairajan I.} and Scott Lindhorst and Michal Yalon and Gary Mason and Bruce Crooks and Shlomi Constantini and Maura Massimino and Stefano Chiaravalli and Jagadeesh Ramdas and Warren Mason and Shamvil Ashraf and Roula Farah and {Van Damme}, An and Enrico Opocher and Hamid, {Syed Ahmer} and Ziegler, {David S.} and David Samuel and Cole, {Kristina A.} and Patrick Tomboc and Duncan Stearns and Thomas, {Gregory A.} and Alexander Lossos and Michael Sullivan and Hansford, {Jordan R.} and Alan Mackay and Chris Jones and Jones, {David T.W.} and Vijay Ramaswamy and Cynthia Hawkins and Eric Bouffet and Uri Tabori",

note = "Funding Information: 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{\textquoteright}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{\textquoteright}s Hospital Foundation. Funding Information: 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. Publisher Copyright: {\textcopyright} 2020, Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2020",

month = nov,

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doi = "10.1007/s00401-020-02209-8",

language = "English",

volume = "140",

pages = "765--776",

journal = "Acta Neuropathologica",

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T1 - Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns

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

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - 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.

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.

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

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