The molecular landscape of ETMR at diagnosis and relapse

被引：99

作者：

Lambo, Sander ^{[1
,2
,3
]}

Groebner, Susanne N. ^{[1
,2
,3
]}

Rausch, Tobias ^{[4
]}

Waszak, Sebastian M. ^{[4
]}

Schmidt, Christin ^{[1
,2
,3
]}

Gorthi, Aparna ^{[5
,6
]}

Romero, July Carolina ^{[5
,6
]}

Mauermann, Monika ^{[1
,2
,3
]}

Brabetz, Sebastian ^{[1
,2
,3
]}

Krausert, Sonja ^{[1
,2
,3
]}

Buchhalter, Ivo ^{[7
]}

Koster, Jan ^{[8
]}

Zwijnenburg, Danny A. ^{[8
]}

Sill, Martin ^{[1
,2
,3
]}

Huebner, Jens-Martin ^{[1
,2
,3
]}

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

Schwalm, Benjamin ^{[1
,2
,3
]}

Ryzhova, Marina ^{[9
]}

Hovestadt, Volker ^{[10
]}

Papillon-Cavanagh, Simon ^{[11
]}

Chan, Jennifer A. ^{[12
]}

Landgraf, Pablo ^{[13
,14
]}

Ho, Ben ^{[15
]}

Milde, Till ^{[13
,14
,16
,17
]}

Witt, Olaf ^{[1
,16
,17
]}

Ecker, Jonas ^{[1
,16
,17
]}

Sahm, Felix ^{[1
,3
,18
,19
]}

Sumerauer, David ^{[20
]}

Ellison, David W. ^{[21
]}

Orr, Brent A. ^{[21
]}

Darabi, Anna ^{[22
]}

Haberler, Christine ^{[23
]}

Figarella-Branger, Dominique ^{[24
,25
]}

Wesseling, Pieter ^{[26
,27
]}

Schittenhelm, Jens ^{[28
,29
]}

Remke, Marc ^{[3
,30
,31
]}

Taylor, Michael D. ^{[31
]}

Gil-da-Costa, Maria J. ^{[32
]}

Lastowska, Maria ^{[33
]}

Grajkowska, Wieslawa ^{[33
]}

Hasselblatt, Martin ^{[34
]}

Hauser, Peter ^{[35
]}

Pietsch, Torsten ^{[36
]}

Uro-Coste, Emmanuelle ^{[37
,38
]}

Bourdeaut, Franck ^{[39
]}

Masliah-Planchon, Julien ^{[40
,41
]}

Rigau, Valerie ^{[42
,43
]}

Alexandrescu, Sanda ^{[44
]}

Wolf, Stephan ^{[45
]}

Li, Xiao-Nan ^{[46
,47
,48
]}

机构：

[1] Hopp Childrens Canc Ctr KiTZ, Heidelberg, Germany

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

[3] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

[4] European Mol Biol Lab, Genome Biol Unit, Heidelberg, Germany

[5] Univ Texas Hlth San Antonio, Dept Cell Syst & Anat, San Antonio, TX USA

[6] Univ Texas Hlth San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX USA

[7] German Canc Res Ctr, Omics IT & Data Management Core Facil, Heidelberg, Germany

[8] Acad Med Ctr, Dept Oncogenom, Amsterdam, Netherlands

[9] NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow, Russia

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

[11] McGill Univ, Ctr Hlth, Dept Pediat, Montreal, PQ, Canada

[12] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB, Canada

[13] Univ Cologne, Fac Med, Dept Pediat Pediat Oncol & Hematol, Cologne, Germany

[14] Univ Cologne, Univ Hosp Cologne, Cologne, Germany

[15] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Div Hematol Oncol, Toronto, ON, Canada

[16] German Canc Res Ctr, Clin Cooperat Unit Pediat Oncol, Heidelberg, Germany

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

[18] Heidelberg Univ Hosp, Dept Neuropathol, Heidelberg, Germany

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

[20] Univ Hosp Motol, Dept Pediat Hematol & Oncol, Prague, Czech Republic

[21] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA

[22] Lund Univ, Fac Med, Dept Clin Sci Lund, Neurosurg Sect, Lund, Sweden

[23] Med Univ Vienna, Inst Neurol, Vienna, Austria

[24] Aix Marseille Univ, Neurophysiopathol Inst INP, CNRS, Marseille, France

[25] APHM, Dept Pathol, Marseille, France

[26] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands

[27] Univ Amsterdam, Med Ctr Locat VUmc, Dept Pathol, Amsterdam, Netherlands

[28] Univ Hosp Tubingen, Inst Pathol & Neuropathol, Dept Neuropathol, Tubingen, Germany

[29] Univ Hosp Tubingen, Comprehens Canc Ctr Tubingen Stuttgart, Ctr CNS Tumors, Tubingen, Germany

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

[31] Univ Toronto, Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Div Neurosurg, Toronto, ON, Canada

[32] Univ Hosp Sao Joao Alameda Hernani Monteiro, Pediat Hematol & Oncol Div, Porto, Portugal

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

[34] Univ Hosp Munster, Inst Neuropathol, Munster, Germany

[35] Semmelweis Univ, Dept Pediat 2, Budapest, Hungary

[36] Univ Bonn, German Soc Neuropathol & Neuroanat, Brain Tumor Reference Ctr, Inst Neuropathol,Med Ctr, Bonn, Germany

[37] Toulouse Univ Hosp, Dept Pathol, Toulouse, France

[38] CRCT, INSERM, U1037, Toulouse, France

[39] Paris Sci Lettres Res Univ, Lab Translat Res Pediat Oncol, SIREDO Pediat Oncol Ctr, Inst Curie,INSERM,U830, Paris, France

[40] Curie Inst, SIREDO Pediat Oncol Ctr, Dept Pediat Oncol, Paris, France

[41] Paris Sci & Lettres Res Univ, Inst Curie Hosp, Lab Somat Genet, Paris, France

[42] Montpellier Univ, Med Ctr, Dept Pathol, Montpellier, France

[43] Montpellier Univ Hosp, INM, INSERM, U1051, Montpellier, France

[44] Harvard Med Sch, Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA

[45] German Canc Res Ctr, High Throughput Sequencing Unit, Genom & Prote Core Facil, Heidelberg, Germany

[46] Baylor Coll Med, Dept Pediat, Texas Childrens Canc Ctr, Brain Tumor Program, Houston, TX 77030 USA

[47] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA

[48] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA

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

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

来源：

NATURE | 2019年 / 576卷 / 7786期

关键词：

DNA-DAMAGE; ABUNDANT NEUROPIL; EMBRYONAL TUMOR; R-LOOPS; RNA; MEDULLOBLASTOMA; EXPRESSION; DICER1; CLASSIFICATION; CHROMOTHRIPSIS;

D O I：

10.1038/s41586-019-1815-x

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：

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis(1). Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC(2-4) was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.

引用

页码：274 / +

页数：26

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