Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma

Paul A. Northcott; Yukiko Nakahara; Xiaochong Wu; Lars Feuk; David W. Ellison; Sid Croul; Stephen Mack; Paul N. Kongkham; John Peacock; Adrian Dubuc; Young Shin Ra; Karen Zilberberg; Jessica Mcleod; Stephen W. Scherer; J. Sunil Rao; Charles G. Eberhart; Wiesia Grajkowska; Yancey Gillespie; Boleslaw Lach; Richard Grundy; Ian F. Pollack; Ronald L. Hamilton; Timothy Van Meter; Carlos G. Carlotti; Frederick Boop; Darrell Bigner; Richard J. Gilbertson; James T. Rutka; Michael D. Taylor

doi:10.1038/ng.336

Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma

Paul A. Northcott, Yukiko Nakahara, Xiaochong Wu, Lars Feuk, David W. Ellison, Sid Croul, Stephen Mack, Paul N. Kongkham, John Peacock, Adrian Dubuc, Young Shin Ra, Karen Zilberberg, Jessica Mcleod, Stephen W. Scherer, J. Sunil Rao, Charles G. Eberhart, Wiesia Grajkowska, Yancey Gillespie, Boleslaw Lach, Richard GrundyIan F. Pollack, Ronald L. Hamilton, Timothy Van Meter, Carlos G. Carlotti, Frederick Boop, Darrell Bigner, Richard J. Gilbertson, James T. Rutka, Michael D. Taylor

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

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Abstract

We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.

Original language	English (US)
Pages (from-to)	465-472
Number of pages	8
Journal	Nature Genetics
Volume	41
Issue number	4
DOIs	https://doi.org/10.1038/ng.336
State	Published - Apr 2009
Externally published	Yes

Bibliographical note

Funding Information:
We thank the individuals and families who agreed to take part in these studies. We thank S. Egan, J. Ellis and R. Bremner for critical review of the manuscript. We thank R. Wechsler-Reya (Duke), A.M. Kenney (Memorial-Sloan Kettering) and D. Rowitch (University of California San Francisco) for reagents and helpful discussions. We are grateful to K. Helin (University of Copenhagen) for providing JMJD2C expression constructs. We thank P. Paroutis for artwork and S. Archer for editing. We are grateful to C. Marshall and J. Wei for assistance with copy number analysis. This work was supported by the Canadian Cancer Society and the Pediatric Brain Tumor Foundation. M.D.T. is supported by a Sontag Foundation Distinguished Scholar award. Additional research support was obtained from the Hospital for Sick Children Foundation, The Neurosurgery Research and Education Foundation, BRAINCHILD, the 407 Express Toll Route, and the Walker family. M.D.T. was supported by the Laurie Berman fund in Brain Tumor Research, the American Brain Tumor Association and a Clinician-Scientist award from the Canadian Institutes of Health Research. P.A.N. was supported by a Restracomp salary award from the Hospital for Sick Children.

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Northcott, P. A., Nakahara, Y., Wu, X., Feuk, L., Ellison, D. W., Croul, S., Mack, S., Kongkham, P. N., Peacock, J., Dubuc, A., Ra, Y. S., Zilberberg, K., Mcleod, J., Scherer, S. W., Sunil Rao, J., Eberhart, C. G., Grajkowska, W., Gillespie, Y., Lach, B., ... Taylor, M. D. (2009). Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nature Genetics, 41(4), 465-472. https://doi.org/10.1038/ng.336

Northcott, PA, Nakahara, Y, Wu, X, Feuk, L, Ellison, DW, Croul, S, Mack, S, Kongkham, PN, Peacock, J, Dubuc, A, Ra, YS, Zilberberg, K, Mcleod, J, Scherer, SW, Sunil Rao, J, Eberhart, CG, Grajkowska, W, Gillespie, Y, Lach, B, Grundy, R, Pollack, IF, Hamilton, RL, Van Meter, T, Carlotti, CG, Boop, F, Bigner, D, Gilbertson, RJ, Rutka, JT & Taylor, MD 2009, 'Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma', Nature Genetics, vol. 41, no. 4, pp. 465-472. https://doi.org/10.1038/ng.336

@article{704729b03c014611af4dd5381dfab4fc,

title = "Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma",

abstract = "We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.",

author = "Northcott, {Paul A.} and Yukiko Nakahara and Xiaochong Wu and Lars Feuk and Ellison, {David W.} and Sid Croul and Stephen Mack and Kongkham, {Paul N.} and John Peacock and Adrian Dubuc and Ra, {Young Shin} and Karen Zilberberg and Jessica Mcleod and Scherer, {Stephen W.} and {Sunil Rao}, J. and Eberhart, {Charles G.} and Wiesia Grajkowska and Yancey Gillespie and Boleslaw Lach and Richard Grundy and Pollack, {Ian F.} and Hamilton, {Ronald L.} and {Van Meter}, Timothy and Carlotti, {Carlos G.} and Frederick Boop and Darrell Bigner and Gilbertson, {Richard J.} and Rutka, {James T.} and Taylor, {Michael D.}",

note = "Funding Information: We thank the individuals and families who agreed to take part in these studies. We thank S. Egan, J. Ellis and R. Bremner for critical review of the manuscript. We thank R. Wechsler-Reya (Duke), A.M. Kenney (Memorial-Sloan Kettering) and D. Rowitch (University of California San Francisco) for reagents and helpful discussions. We are grateful to K. Helin (University of Copenhagen) for providing JMJD2C expression constructs. We thank P. Paroutis for artwork and S. Archer for editing. We are grateful to C. Marshall and J. Wei for assistance with copy number analysis. This work was supported by the Canadian Cancer Society and the Pediatric Brain Tumor Foundation. M.D.T. is supported by a Sontag Foundation Distinguished Scholar award. Additional research support was obtained from the Hospital for Sick Children Foundation, The Neurosurgery Research and Education Foundation, BRAINCHILD, the 407 Express Toll Route, and the Walker family. M.D.T. was supported by the Laurie Berman fund in Brain Tumor Research, the American Brain Tumor Association and a Clinician-Scientist award from the Canadian Institutes of Health Research. P.A.N. was supported by a Restracomp salary award from the Hospital for Sick Children.",

year = "2009",

month = apr,

doi = "10.1038/ng.336",

language = "English (US)",

volume = "41",

pages = "465--472",

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T1 - Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma

AU - Northcott, Paul A.

AU - Nakahara, Yukiko

AU - Wu, Xiaochong

AU - Feuk, Lars

AU - Ellison, David W.

AU - Croul, Sid

AU - Mack, Stephen

AU - Kongkham, Paul N.

AU - Peacock, John

AU - Dubuc, Adrian

AU - Ra, Young Shin

AU - Zilberberg, Karen

AU - Mcleod, Jessica

AU - Scherer, Stephen W.

AU - Sunil Rao, J.

AU - Eberhart, Charles G.

AU - Grajkowska, Wiesia

AU - Gillespie, Yancey

AU - Lach, Boleslaw

AU - Grundy, Richard

AU - Pollack, Ian F.

AU - Hamilton, Ronald L.

AU - Van Meter, Timothy

AU - Carlotti, Carlos G.

AU - Boop, Frederick

AU - Bigner, Darrell

AU - Gilbertson, Richard J.

AU - Rutka, James T.

AU - Taylor, Michael D.

N1 - Funding Information: We thank the individuals and families who agreed to take part in these studies. We thank S. Egan, J. Ellis and R. Bremner for critical review of the manuscript. We thank R. Wechsler-Reya (Duke), A.M. Kenney (Memorial-Sloan Kettering) and D. Rowitch (University of California San Francisco) for reagents and helpful discussions. We are grateful to K. Helin (University of Copenhagen) for providing JMJD2C expression constructs. We thank P. Paroutis for artwork and S. Archer for editing. We are grateful to C. Marshall and J. Wei for assistance with copy number analysis. This work was supported by the Canadian Cancer Society and the Pediatric Brain Tumor Foundation. M.D.T. is supported by a Sontag Foundation Distinguished Scholar award. Additional research support was obtained from the Hospital for Sick Children Foundation, The Neurosurgery Research and Education Foundation, BRAINCHILD, the 407 Express Toll Route, and the Walker family. M.D.T. was supported by the Laurie Berman fund in Brain Tumor Research, the American Brain Tumor Association and a Clinician-Scientist award from the Canadian Institutes of Health Research. P.A.N. was supported by a Restracomp salary award from the Hospital for Sick Children.

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N2 - We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.

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Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma

Abstract

Bibliographical note

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