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

被引：328

作者：

Northcott, Paul A. ^{[1
,2
,3
]}

Nakahara, Yukiko ^{[1
,2
]}

Wu, Xiaochong ^{[1
,2
]}

Feuk, Lars ^{[4
,5
]}

Ellison, David W. ^{[6
]}

Croul, Sid ^{[7
]}

Mack, Stephen ^{[1
,2
,3
]}

Kongkham, Paul N. ^{[1
,3
]}

Peacock, John ^{[1
,2
]}

Dubuc, Adrian ^{[1
,2
,3
]}

Ra, Young-Shin ^{[1
]}

Zilberberg, Karen ^{[1
,2
,3
]}

Mcleod, Jessica ^{[1
,2
]}

Scherer, Stephen W. ^{[4
,5
]}

Rao, J. Sunil ^{[8
]}

Eberhart, Charles G. ^{[9
]}

Grajkowska, Wiesia ^{[10
]}

Gillespie, Yancey ^{[11
]}

Lach, Boleslaw ^{[12
]}

Grundy, Richard ^{[13
]}

Pollack, Ian F. ^{[14
]}

Hamilton, Ronald L. ^{[15
]}

Van Meter, Timothy ^{[16
]}

Carlotti, Carlos G. ^{[17
]}

Boop, Frederick ^{[18
]}

Bigner, Darrell ^{[19
]}

Gilbertson, Richard J. ^{[20
,21
]}

Rutka, James T. ^{[1
,3
]}

Taylor, Michael D. ^{[1
,2
,3
]}

机构：

[1] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Div Neurosurg, Toronto, ON M5G 1X8, Canada

[2] Hosp Sick Children, Program Dev & Stem Cell Biol, Toronto, ON M5G 1X8, Canada

[3] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[4] Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada

[5] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[6] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA

[7] Univ Toronto, Dept Pathol, Univ Hlth Network, Toronto, ON, Canada

[8] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA

[9] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA

[10] Childrens Mem Hlth Inst, Dept Pathol, Warsaw, Poland

[11] Univ Alabama, Dept Surg, Birmingham, AL 35294 USA

[12] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada

[13] Univ Nottingham, Nottingham NG7 2RD, England

[14] Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Neurosurg, Pittsburgh, PA 15213 USA

[15] Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA

[16] Virginia Commonwealth Univ, Med Coll Virginia, Dept Neurosurg, Richmond, VA 23298 USA

[17] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Surg, Div Neurosurg, Sao Paulo, Brazil

[18] St Jude Childrens Hosp, Div Pediat Neurosurg, Memphis, TN 38105 USA

[19] Duke Univ, Dept Pathol, Durham, NC 27706 USA

[20] St Jude Childrens Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA

[21] St Jude Childrens Hosp, Dept Oncol, Memphis, TN 38105 USA

来源：

NATURE GENETICS | 2009年 / 41卷 / 04期

基金：

加拿大健康研究院;

关键词：

COMPARATIVE GENOMIC HYBRIDIZATION; SMALL-MOLECULE INHIBITOR; CEREBELLAR DEVELOPMENT; COMPLEX; CELLS; DIFFERENTIATION; ABNORMALITIES; TRANSCRIPTION; LEUKEMIA; PROTEIN;

D O I：

10.1038/ng.336

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：465 / 472

页数：8

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