Spatial heterogeneity in medulloblastoma

被引：101

作者：

Morrissy, A. Sorana ^{[1
,2
]}

Cavalli, Florence M. G. ^{[1
,2
]}

Remke, Marc ^{[1
,2
,3
,4
,5
,6
]}

Ramaswamy, Vijay ^{[1
,2
,7
]}

Shih, David J. H. ^{[1
,2
,8
]}

Holgado, Borja L. ^{[1
,2
]}

Farooq, Hamza ^{[1
,2
,8
]}

Donovan, Laura K. ^{[1
,2
]}

Garzia, Livia ^{[1
,2
,9
]}

Agnihotri, Sameer ^{[10
]}

Kiehna, Erin N. ^{[11
]}

Mercier, Eloi ^{[12
]}

Mayoh, Chelsea ^{[12
]}

Papillon-Cavanagh, Simon ^{[13
,14
]}

Nikbakht, Hamid ^{[13
,14
]}

Gayden, Tenzin ^{[13
,14
]}

Torchia, Jonathon ^{[2
,7
,8
]}

Picard, Daniel ^{[3
,4
,5
,6
]}

Merino, Diana M. ^{[2
,7
,15
]}

Vladoiu, Maria ^{[1
,2
]}

Luu, Betty ^{[1
,2
]}

Wu, Xiaochong ^{[1
,2
]}

Daniels, Craig ^{[1
,2
]}

Horswell, Stuart ^{[16
]}

Thompson, Yuan Yao ^{[1
,2
,8
]}

Hovestadt, Volker ^{[17
]}

Northcott, Paul A. ^{[18
]}

Jones, David T. W. ^{[18
]}

Peacock, John ^{[1
,2
,8
]}

Wang, Xin ^{[1
,2
,8
]}

Mack, Stephen C. ^{[1
,2
,8
]}

Reimand, Juri ^{[19
,20
,21
]}

Albrecht, Steffen ^{[22
]}

Fontebasso, Adam M. ^{[23
]}

Thiessen, Nina ^{[12
]}

Li, Yisu ^{[12
]}

Schein, Jacqueline E. ^{[12
]}

Lee, Darlene ^{[12
]}

Carlsen, Rebecca ^{[12
]}

Mayo, Michael ^{[12
]}

Tse, Kane ^{[12
]}

Tam, Angela ^{[12
]}

Dhalla, Noreen ^{[12
]}

Ally, Adrian ^{[12
]}

Chuah, Eric ^{[12
]}

Cheng, Young ^{[12
]}

Plettner, Patrick ^{[12
]}

Li, Haiyan I. ^{[12
]}

Corbett, Richard D. ^{[12
]}

Wong, Tina ^{[12
]}

机构：

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

[2] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada

[3] Univ Hosp Dusseldorf, Fac Med, Dept Pediat Oncol Hematol & Clin Immunol, Dusseldorf, Germany

[4] Univ Hosp Dusseldorf, Fac Med, Dept Neuropathol, Dusseldorf, Germany

[5] German Canc Consortium DKTK, Dept Pediat Neurooncogen, Dusseldorf, Germany

[6] German Canc Res Ctr, Dusseldorf, Germany

[7] Hosp Sick Children, Dept Pediat, Div Haematol Oncol, Toronto, ON, Canada

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

[9] McGill Univ, Ctr Hlth, Res Inst, Canc Res Program, Montreal, PQ, Canada

[10] Univ Hlth Network, Princess Margaret Canc Ctr, MacFeeters Hamilton Brain Tumour Ctr, Toronto, ON, Canada

[11] Hosp Sick Children, Div Neurosurg, Toronto, ON, Canada

[12] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada

[13] McGill Univ, Dept Pediat, Montreal, PQ, Canada

[14] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[15] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON, Canada

[16] Canc Res UK London Res Inst, London, England

[17] German Canc Res Ctr, Div Mol Genet, Heidelberg, Germany

[18] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany

[19] Ontario Inst Canc Res, Informat & Biocomp, Toronto, ON, Canada

[20] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[21] Univ Toronto, Donnelly Ctr, Toronto, ON, Canada

[22] McGill Univ, Ctr Hlth, Montreal Childrens Hosp, Dept Pathol, Montreal, PQ, Canada

[23] McGill Univ, Div Expt Med, Montreal, PQ, Canada

[24] Hosp Sick Children, Div Pathol, Toronto, ON, Canada

[25] Childrens Natl Med Ctr, Div Pediat Oncol, Washington, DC 20010 USA

[26] Childrens Natl Med Ctr, Div Pediat Neurosurg, Washington, DC 20010 USA

[27] Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA

[28] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, Heidelberg, Germany

[29] German Canc Consortium DKTK, Heidelberg, Germany

[30] Univ Hosp Heidelberg, Dept Pediat Oncol Hematol Immunol & Pulmonol, Heidelberg, Germany

[31] Univ Med Ctr, Inst Neuropathol, Hamburg, Germany

[32] Childrens Canc Ctr, Res Inst, Hamburg, Germany

[33] Univ Med Ctr, Pediat Hematol & Oncol, Hamburg, Germany

[34] Francis Crick Inst, Translat Canc Therapeut Lab, London, England

[35] UCL, Canc Res UK Lung Canc Ctr Excellence, London, England

[36] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada

[37] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC, Canada

[38] Univ Toronto, St Michaels Hosp, Div Neurosurg, Toronto, ON, Canada

来源：

NATURE GENETICS | 2017年 / 49卷 / 05期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

RENAL-CELL CARCINOMA; INTRATUMOR HETEROGENEITY; T-CELLS; SOLID TUMORS; IN-VITRO; LYMPHOCYTES; EVOLUTION; GROWTH; EXPRESSION; SUBTYPES;

D O I：

10.1038/ng.3838

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

引用

页码：780 / +

页数：12

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