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 journalArticle

313 Scopus citations

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 languageEnglish (US)
Pages (from-to)465-472
Number of pages8
JournalNature genetics
Volume41
Issue number4
DOIs
StatePublished - Apr 2009

ASJC Scopus subject areas

  • Genetics

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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