The landscape of genomic alterations across childhood cancers

Susanne N. Gröbner, Barbara C. Worst, Joachim Weischenfeldt, Ivo Buchhalter, Kortine Kleinheinz, Vasilisa A. Rudneva, Pascal D. Johann, Gnana Prakash Balasubramanian, Maia Segura-Wang, Sebastian Brabetz, Sebastian Bender, Barbara Hutter, Dominik Sturm, Elke Pfaff, Daniel Hübschmann, Gideon Zipprich, Michael Heinold, Jürgen Eils, Christian Lawerenz, Serap Erkek, Sander Lambo, Sebastian Waszak, Claudia Blattmann, Arndt Borkhardt, Michaela Kuhlen, Angelika Eggert, Simone Fulda, Manfred Gessler, Jenny Wegert, Roland Kappler, Daniel Baumhoer, Stefan Burdach, Renate Kirschner-Schwabe, Udo Kontny, Andreas E. Kulozik, Dietmar Lohmann, Simone Hettmer, Cornelia Eckert, Stefan Bielack, Michaela Nathrath, Charlotte Niemeyer, Günther H. Richter, Johannes Schulte, Reiner Siebert, Frank Westermann, Jan J. Molenaar, Gilles Vassal, Hendrik Witt, Birgit Burkhardt, Christian P. Kratz, Olaf Witt, Cornelis M. van Tilburg, Christof M. Kramm, Gudrun Fleischhack, Uta Dirksen, Stefan Rutkowski, Michael Frühwald, Katja von Hoff, Stephan Wolf, Thomas Klingebiel, Ewa Koscielniak, Pablo Landgraf, Jan Koster, Adam C. Resnick, Jinghui Zhang, Yanling Liu, Xin Zhou, Angela J. Waanders, Danny A. Zwijnenburg, Pichai Raman, Benedikt Brors, Ursula D. Weber, Paul A. Northcott, Kristian W. Pajtler, Marcel Kool, Rosario M. Piro, Jan O. Korbel, Matthias Schlesner, Roland Eils, David T. W. Jones, Peter Lichter, Lukas Chavez, Marc Zapatka and Stefan M. Pfister ()
Additional contact information
Susanne N. Gröbner: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Barbara C. Worst: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Joachim Weischenfeldt: European Molecular Biology Laboratory (EMBL), Genome Biology Unit
Ivo Buchhalter: German Cancer Research Center (DKFZ)
Kortine Kleinheinz: German Cancer Research Center (DKFZ)
Vasilisa A. Rudneva: European Molecular Biology Laboratory (EMBL), Genome Biology Unit
Pascal D. Johann: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Gnana Prakash Balasubramanian: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Maia Segura-Wang: European Molecular Biology Laboratory (EMBL), Genome Biology Unit
Sebastian Brabetz: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Sebastian Bender: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Barbara Hutter: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Dominik Sturm: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Elke Pfaff: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Daniel Hübschmann: Hematology & Immunology, Heidelberg University Hospital
Gideon Zipprich: German Cancer Research Center (DKFZ)
Michael Heinold: German Cancer Research Center (DKFZ)
Jürgen Eils: German Cancer Research Center (DKFZ)
Christian Lawerenz: German Cancer Research Center (DKFZ)
Serap Erkek: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Sander Lambo: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Sebastian Waszak: European Molecular Biology Laboratory (EMBL), Genome Biology Unit
Claudia Blattmann: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Arndt Borkhardt: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Michaela Kuhlen: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Angelika Eggert: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Simone Fulda: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Manfred Gessler: Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, University of Würzburg
Jenny Wegert: Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, University of Würzburg
Roland Kappler: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Daniel Baumhoer: Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel and University of Basel
Stefan Burdach: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Renate Kirschner-Schwabe: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Udo Kontny: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Andreas E. Kulozik: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Dietmar Lohmann: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Simone Hettmer: University Medical Center Freiburg
Cornelia Eckert: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Stefan Bielack: Klinikum Stuttgart - Olgahospital, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pädiatrie
Michaela Nathrath: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Charlotte Niemeyer: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Günther H. Richter: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Johannes Schulte: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Reiner Siebert: Institute of Human Genetics, University of Ulm & University Hospital of Ulm
Frank Westermann: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Jan J. Molenaar: Princess Máxima Center for Pediatric Oncology
Gilles Vassal: Gustave Roussy, Université Paris-Saclay
Hendrik Witt: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Birgit Burkhardt: Pediatric Hematology and Oncology, University Hospital Münster
Christian P. Kratz: Pediatric Hematology and Oncology, Hannover Medical School
Olaf Witt: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Cornelis M. van Tilburg: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Christof M. Kramm: University Medical Center Göttingen
Gudrun Fleischhack: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Uta Dirksen: Pediatric Oncology & Hematology, Pediatrics III, University Hospital of Essen
Stefan Rutkowski: University Medical Center Hamburg-Eppendorf
Michael Frühwald: Swabian Children’s Cancer Center, Children’s Hospital, Klinikum Augsburg
Katja von Hoff: University Medical Center Hamburg-Eppendorf
Stephan Wolf: Genomics and Proteomics Core Facility, High Throughput Sequencing Unit, German Cancer Research Center (DKFZ)
Thomas Klingebiel: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Ewa Koscielniak: Klinikum Stuttgart - Olgahospital, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pädiatrie
Pablo Landgraf: University Hospital Cologne, Klinik und Poliklinik für Kinder- und Jugendmedizin
Jan Koster: Academic Medical Center
Adam C. Resnick: Center for Childhood Cancer Research, Children’s Hospital of Philadelphia
Jinghui Zhang: St Jude Children’s Research Hospital
Yanling Liu: St Jude Children’s Research Hospital
Xin Zhou: St Jude Children’s Research Hospital
Angela J. Waanders: Center for Childhood Cancer Research, Children’s Hospital of Philadelphia
Danny A. Zwijnenburg: Academic Medical Center
Pichai Raman: Center for Childhood Cancer Research, Children’s Hospital of Philadelphia
Benedikt Brors: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Ursula D. Weber: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Paul A. Northcott: German Cancer Research Center (DKFZ)
Kristian W. Pajtler: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Marcel Kool: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Rosario M. Piro: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Jan O. Korbel: European Molecular Biology Laboratory (EMBL), Genome Biology Unit
Matthias Schlesner: German Cancer Research Center (DKFZ)
Roland Eils: German Cancer Research Center (DKFZ)
David T. W. Jones: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Peter Lichter: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Lukas Chavez: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Marc Zapatka: German Cancer Research Center (DKFZ)
Stefan M. Pfister: Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)

Nature, 2018, vol. 555, issue 7696, 321-327

Abstract: Abstract 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.

Date: 2018
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Citations: View citations in EconPapers (12)

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DOI: 10.1038/nature25480

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