Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

被引：443

作者：

Mack, S. C. ^{[1
,2
,3
]}

Witt, H. ^{[4
,5
,6
]}

Piro, R. M. ^{[6
,7
]}

Gu, L. ^{[6
,8
]}

Zuyderduyn, S. ^{[9
]}

Stuetz, A. M. ^{[6
,10
]}

Wang, X. ^{[1
,2
]}

Gallo, M. ^{[1
]}

Garzia, L. ^{[1
]}

Zayne, K. ^{[1
]}

Zhang, X. ^{[11
]}

Ramaswamy, V. ^{[1
,2
]}

Jaeger, N. ^{[6
,8
]}

Jones, D. T. W. ^{[4
,6
]}

Sill, M. ^{[6
,12
]}

Pugh, T. J. ^{[13
]}

Ryzhova, M. ^{[4
,6
]}

Wani, K. M. ^{[14
]}

Shih, D. J. H. ^{[1
,2
]}

Head, R. ^{[1
]}

Remke, M. ^{[1
,2
]}

Bailey, S. D. ^{[15
,16
]}

Zichner, T. ^{[6
,10
]}

Faria, C. C. ^{[1
]}

Barszczyk, M. ^{[1
,2
]}

Stark, S. ^{[4
,6
]}

Seker-Cin, H. ^{[4
,6
]}

Hutter, S. ^{[4
,6
]}

Johann, P. ^{[4
,6
]}

Bender, S. ^{[4
,6
]}

Hovestadt, V. ^{[6
,7
]}

Tzaridis, T. ^{[4
,6
]}

Dubuc, A. M. ^{[1
,2
]}

Northcott, P. A. ^{[4
,6
]}

Peacock, J. ^{[1
,2
]}

Bertrand, K. C. ^{[1
,2
]}

Agnihotri, S. ^{[1
]}

Cavalli, F. M. G. ^{[1
]}

Clarke, I. ^{[1
]}

Nethery-Brokx, K. ^{[1
]}

Creasy, C. L. ^{[17
]}

Verma, S. K. ^{[17
]}

Koster, J. ^{[18
]}

Wu, X. ^{[1
]}

Yao, Y. ^{[1
,2
]}

Milde, T. ^{[5
,6
,19
]}

Sin-Chan, P. ^{[1
]}

Zuccaro, J. ^{[1
]}

Lau, L. ^{[1
]}

Pereira, S. ^{[1
]}

机构：

[1] Hosp Sick Children, Dev & Stem Cell Biol Program, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1L7, Canada

[2] Univ Toronto, Toronto, ON M5S 1A8, Canada

[3] Univ Toronto, Div Neurosurg, Toronto, ON M5S 1A8, Canada

[4] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany

[5] Heidelberg Univ, Dept Pediat Oncol Hematol & Immunol, D-69120 Heidelberg, Germany

[6] German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[7] German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany

[8] German Canc Res Ctr, Div Theoret Bioinformat, D-69120 Heidelberg, Germany

[9] Univ Toronto, Donnelly Ctr, Banting & Best Dept Med Res, Dept Mol Genet, Toronto, ON M4N 1X8, Canada

[10] European Mol Biol, Genome Biol, D-69117 Heidelberg, Germany

[11] Dartmouth Med Sch, Norris Cotton Canc Ctr, Dept Genet, Lebanon, NH 03756 USA

[12] German Canc Res Ctr, Div Bioinformat, D-69120 Heidelberg, Germany

[13] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Neurol,MIT, Boston, MA 02115 USA

[14] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[15] Univ Hlth Network, Princess Margaret Canc Ctr, Ontario Canc Inst, Toronto, ON M5G 1L7, Canada

[16] Ontario Inst Canc Res, Toronto, ON M5G 1L7, Canada

[17] GlaxoSmithKline, Canc Epigenet Discovery Performance Unit, Collegeville, PA 19426 USA

[18] Acad Med Ctr, Dept Oncogen, NL-1105 Amsterdam, Netherlands

[19] German Canc Res Ctr, CCU Pediat Oncol, D-69120 Heidelberg, Germany

[20] Univ British Columbia, Dept Microbiol & Immunol, Ctr High Throughput Biol, Vancouver, BC V6T 1Z4, Canada

[21] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada

[22] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada

[23] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA

[24] Uniformed Serv Univ Hlth Sci, Natl Capital Consortium, Bethesda, MD 20814 USA

[25] Univ Utah, Sch Med, Dept Neurosurg, Salt Lake City, UT 84132 USA

[26] Univ Cattolica Sacro Cuore, Sch Med, Gemelli Hosp, I-00168 Rome, Italy

[27] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[28] Virginia Commonwealth, Dept Pediat, Richmond, VA 23298 USA

[29] Univ Warsaw, Dept Pathol, Childrens Mem Hlth Inst, PL-04730 Warsaw, Poland

[30] McMaster Univ, Hamilton Gen Hosp, Div Anat Pathol, Dept Pathol & Mol Med, Hamilton, ON L8S 4K1, Canada

[31] Heidelberg Univ, Inst Pathol, Dept Neuropathol, D-69120 Heidelberg, Germany

[32] Univ Michigan Cell & Dev Biol, Ann Arbor, MI 48109 USA

[33] Univ Michigan, Sch Med, Dept Neurosurg, Ann Arbor, MI 48109 USA

[34] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA

[35] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA

[36] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA

[37] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94158 USA

[38] Hosp Sick Children, Dept Neurooncol, Toronto, ON M5G 1X8, Canada

[39] Hosp Sick Children, Dept Haematol & Oncol, Toronto, ON M5G 1X8, Canada

[40] McGill Univ, Dept Pediat, Montreal, PQ H3Z 2Z3, Canada

[41] McGill Univ, Dept Human Genet, Montreal, PQ H3Z 2Z3, Canada

[42] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ H3Z 2Z3, Canada

[43] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1X8, Canada

[44] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[45] German Canc Res Ctr, CCU Neuropathol, D-69120 Heidelberg, Germany

来源：

NATURE | 2014年 / 506卷 / 7489期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

ISLAND METHYLATOR PHENOTYPE; GENE-EXPRESSION SIGNATURE; DRIVER MUTATIONS; GENOMIC COMPLEXITY; DISTINCT SUBGROUPS; CANCER; LANDSCAPE; STRATEGY; SUBTYPE;

D O I：

10.1038/nature13108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

引用

页码：445 / +

页数：9

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