The landscape of genomic alterations across childhood cancers

被引：1063

作者：

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

Worst, Barbara C. ^{[1
,2
,3
,4
]}

Weischenfeldt, Joachim ^{[5
,6
]}

Buchhalter, Ivo ^{[7
]}

Kleinheinz, Kortine ^{[7
]}

Rudneva, Vasilisa A. ^{[5
,8
]}

Johann, Pascal D. ^{[1
,2
,3
,4
]}

Balasubramanian, Gnana Prakash ^{[1
,2
,9
]}

Segura-Wang, Maia ^{[5
]}

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

Bender, Sebastian ^{[1
,2
]}

Hutter, Barbara ^{[3
,7
,9
]}

Sturm, Dominik ^{[1
,2
,3
,4
]}

Pfaff, Elke ^{[1
,2
,3
,4
]}

Huebschmann, Daniel ^{[4
,9
,10
,11
]}

Zipprich, Gideon ^{[7
]}

Heinold, Michael ^{[7
,10
,11
]}

Eils, Jurgen ^{[7
]}

Lawerenz, Christian ^{[7
]}

Erkek, Serap ^{[1
,2
,3
,5
]}

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

Waszak, Sebastian ^{[5
]}

Blattmann, Claudia ^{[3
,12
]}

Borkhardt, Arndt ^{[3
,13
]}

Kuhlen, Michaela ^{[3
,13
]}

Eggert, Angelika ^{[3
,14
]}

Fulda, Simone ^{[3
,15
]}

Gessler, Manfred ^{[16
]}

Wegert, Jenny ^{[16
]}

Kappler, Roland ^{[3
,17
]}

Baumhoer, Daniel ^{[18
,19
]}

Burdach, Stefan ^{[3
,20
,21
]}

Kirschner-Schwabe, Renate ^{[3
,14
]}

Kontny, Udo ^{[3
,22
]}

Kulozik, Andreas E. ^{[1
,3
,4
]}

Lohmann, Dietmar ^{[3
,23
]}

Hettmer, Simone ^{[24
]}

Eckert, Cornelia ^{[3
,14
]}

Bielack, Stefan ^{[12
]}

Nathrath, Michaela ^{[3
,20
,21
,25
]}

Niemeyer, Charlotte ^{[3
,24
]}

Richter, Gunther H. ^{[3
,20
,21
]}

Schulte, Johannes ^{[3
,14
]}

Siebert, Reiner ^{[26
,27
]}

Westermann, Frank ^{[3
,28
]}

Molenaar, Jan J. ^{[29
]}

Vassal, Gilles ^{[30
,31
]}

Witt, Hendrik ^{[1
,2
,3
,4
]}

Burkhardt, Birgit ^{[32
]}

Kratz, Christian P. ^{[33
]}

机构：

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

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

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

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

[5] European Mol Biol Lab EMBL, Genome Biol Unit, Heidelberg, Germany

[6] Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, Rigshosp, Finsen Lab, Copenhagen, Denmark

[7] German Canc Res Ctr, Div Theoret Bioinformat, Heidelberg, Germany

[8] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN USA

[9] German Canc Res Ctr, Div Appl Bioinformat, Heidelberg, Germany

[10] Heidelberg Univ, Inst Pharm & Mol Biotechnol, Dept Bioinformat & Funct Genom, D-69120 Heidelberg, Germany

[11] BioQuant Ctr, D-69120 Heidelberg, Germany

[12] Klinikum Stuttgart Olgahosp, Zentrum Kinder Jugend & Frauenmed, Padiatrie, Stuttgart, Germany

[13] Heinrich Heine Univ, Univ Childrens Hosp, Dept Pediat Oncol Hematol & Clin Immunol, Dusseldorf, Germany

[14] Charite Univ Med Berlin, Dept Pediat Oncol Hematol, Berlin, Germany

[15] Univ Hosp Frankfurt, Inst Expt Canc Res Pediat, Frankfurt, Germany

[16] Univ Wurzburg, Mainfranken, Dev Biochem & Comprehens Canc Ctr, Theodor Boveri Inst Bioctr, Wurzburg, Germany

[17] Ludwig Maximilians Univ Munchen, Dr Von Hauner Childrens Hosp, Res Labs, Dept Pediat Surg, Munich, Germany

[18] Univ Basel Hosp, Inst Pathol, Bone Tumor Reference Ctr, Basel, Switzerland

[19] Univ Basel, Basel, Switzerland

[20] Tech Univ Munich, Klinikum Rechts Isar, Childrens Canc Res Ctr, Munich, Germany

[21] Tech Univ Munich, Dept Pediat, Klinikum Rechts Isar, Munich, Germany

[22] Univ Med Ctr Aachen, Div Pediat Hematol & Oncol, Aachen, Germany

[23] Univ Hosp Essen, Dept Human Genet, Essen, Germany

[24] Univ Med Ctr Freiburg, Dept Pediat, Div Pediat Hematol & Oncol, Freiburg, Germany

[25] Klinikum Kassel, Dept Pediat Oncol, Kassel, Germany

[26] Univ Ulm, Inst Human Genet, Ulm, Germany

[27] Univ Hosp Ulm, Ulm, Germany

[28] German Canc Res Ctr, Div Neuroblastoma Genom, Heidelberg, Germany

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

[30] Univ Paris Saclay, Gustave Roussy, Innovat Therapies Children Canc Consortium, Villejuif, France

[31] Univ Paris Saclay, Gustave Roussy, Dept Clin Res, Villejuif, France

[32] Univ Hosp Munster, Pediat Hematol & Oncol, Munster, Germany

[33] Hannover Med Sch, Pediat Hematol & Oncol, Hannover, Germany

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

[35] Univ Hosp, Ctr Individualized Pediat Oncol ZIPO & Brain Tumo, Heidelberg, Germany

[36] German Canc Res Ctr, Heidelberg, Germany

[37] Univ Med Ctr Gottingen, Div Pediat Hematol & Oncol, Gottingen, Germany

[38] Univ Hosp Essen, Pediat Oncol & Hematol, Pediat 3, Essen, Germany

[39] Univ Med Ctr Hamburg Eppendorf, Dept Pediat Hematol & Oncol, Hamburg, Germany

[40] Klinikum Augsburg, Childrens Hosp, Swabian Childrens Canc Ctr, Augsburg, Germany

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

[42] Univ Hosp Frankfurt, Hosp Children & Adolescents, Frankfurt, Germany

[43] Univ Hosp Cologne, Klin & Poliklin Kinder & Jugendmed, Cologne, Germany

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

[45] Childrens Hosp Philadelphia, Div Neurosurg, Dept Biomed & Hlth Informat, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA

[46] Childrens Hosp Philadelphia, Ctr Data Driven Discovery Biomed, Philadelphia, PA USA

[47] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA

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

[49] Free Univ Berlin, Inst Comp Sci, Berlin, Germany

[50] Charite, Inst Med Genet & Human Genet, Berlin, Germany

来源：

NATURE | 2018年 / 555卷 / 7696期

基金：

欧洲研究理事会;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; MUTATIONAL PROCESSES; PEDIATRIC CANCER; COPY NUMBER; DISTINCT SUBGROUPS; SOMATIC MUTATIONS; SIGNATURES; REVEALS; TARGET; FUSION;

D O I：

10.1038/nature25480

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：

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.

引用

页码：321 / +

页数：23

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