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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 321-327 |
| Number of pages | 7 |
| Journal | Nature |
| Volume | 555 |
| Issue number | 7696 |
| DOIs | |
| State | Published - Mar 15 2018 |
Funding
321 327 10.1038/nature25480 EN Susanne N. Gröbner Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Barbara C. Worst Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany Joachim Weischenfeldt European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany The Finsen Laboratory, Rigshospitalet, Biotech Research and Innovation Centre (BRIC), Copenhagen University, Copenhagen, Denmark Ivo Buchhalter Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Kortine Kleinheinz Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Vasilisa A. Rudneva European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA Pascal D. Johann Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany Gnana Prakash Balasubramanian Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Maia Segura-Wang European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany Sebastian Brabetz Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Sebastian Bender Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany Barbara Hutter German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Dominik Sturm Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany Elke Pfaff Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany Daniel Hübschmann Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University and BioQuant Center, 69120, Heidelberg, Germany Gideon Zipprich Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Michael Heinold Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University and BioQuant Center, 69120, Heidelberg, Germany Jürgen Eils Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Christian Lawerenz Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Serap Erkek Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany Sander Lambo Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Sebastian Waszak European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany Claudia Blattmann German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Klinikum Stuttgart - Olgahospital, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pädiatrie, Stuttgart, Germany Arndt Borkhardt German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Clinical Immunology, University Children’s Hospital, Heinrich Heine University, Düsseldorf, Germany Michaela Kuhlen German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Clinical Immunology, University Children’s Hospital, Heinrich Heine University, Düsseldorf, Germany Angelika Eggert German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany Simone Fulda German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Institute for Experimental Cancer Research in Pediatrics, University Hospital Frankfurt, Frankfurt am Main, Germany Manfred Gessler Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany Jenny Wegert Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany Roland Kappler German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Surgery, Research Laboratories, Dr von Hauner Children’s Hospital, Ludwig Maximilians University Munich, Munich, Germany Daniel Baumhoer Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel and University of Basel, Basel, Switzerland Stefan Burdach German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Children’s Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Renate Kirschner-Schwabe German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany Udo Kontny German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Pediatric Hematology and Oncology, University Medical Center Aachen, Aachen, Germany Andreas E. Kulozik Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany Dietmar Lohmann German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Human Genetics, University Hospital Essen, Essen, Germany Simone Hettmer Division of Pediatric Hematology and Oncology, Department of Pediatrics, University Medical Center Freiburg, Freiburg, Germany Cornelia Eckert German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany Stefan Bielack Klinikum Stuttgart - Olgahospital, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pädiatrie, Stuttgart, Germany Michaela Nathrath German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Children’s Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany Charlotte Niemeyer German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Pediatric Hematology and Oncology, Department of Pediatrics, University Medical Center Freiburg, Freiburg, Germany Günther H. Richter German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Children’s Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Johannes Schulte German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany Reiner Siebert Institute of Human Genetics, University of Ulm & University Hospital of Ulm, Ulm, Germany Frank Westermann German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany Jan J. Molenaar Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands Gilles Vassal Innovative Therapies for Children with Cancer Consortium and Department of Clinical Research, Gustave Roussy, Université Paris-Saclay, Villejuif, France Hendrik Witt Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany ICGC PedBrain-Seq Project ICGC MMML-Seq Project Birgit Burkhardt Pediatric Hematology and Oncology, University Hospital Münster, Münster, Germany Christian P. Kratz Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany Olaf Witt Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany Cornelis M. van Tilburg Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Center for Individualized Pediatric Oncology (ZIPO) and Brain Tumors, University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany Christof M. Kramm Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany Gudrun Fleischhack German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Pediatric Oncology & Hematology, Pediatrics III, University Hospital of Essen, Essen, Germany Uta Dirksen Pediatric Oncology & Hematology, Pediatrics III, University Hospital of Essen, Essen, Germany Stefan Rutkowski Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Michael Frühwald Swabian Children’s Cancer Center, Children’s Hospital, Klinikum Augsburg, Augsburg, Germany Katja von Hoff Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Stephan Wolf Genomics and Proteomics Core Facility, High Throughput Sequencing Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany Thomas Klingebiel German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Hospital for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany Ewa Koscielniak Klinikum Stuttgart - Olgahospital, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pädiatrie, Stuttgart, Germany Pablo Landgraf University Hospital Cologne, Klinik und Poliklinik für Kinder- und Jugendmedizin, Cologne, Germany Jan Koster Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands Adam C. Resnick Division of Neurosurgery, Center for Childhood Cancer Research, Department of Biomedical and Health Informatics and Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Jinghui Zhang Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA Yanling Liu Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA Xin Zhou Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA Angela J. Waanders Division of Oncology, Center for Childhood Cancer Research, Department of Biomedical and Health Informatics and Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, USA Danny A. Zwijnenburg Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands Pichai Raman Division of Neurosurgery, Center for Childhood Cancer Research, Department of Biomedical and Health Informatics and Center for Data-Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Benedikt Brors German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA Ursula D. Weber German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany Paul A. Northcott Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA Kristian W. Pajtler Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany Marcel Kool Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Rosario M. Piro German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany Institute of Computer Science, Freie Universität Berlin, Berlin, Germany Institute of Medical Genetics and Human Genetics, Charité University Hospital, Berlin, Germany Jan O. Korbel European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany Matthias Schlesner Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Bioinformatics and Omics Data Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany Roland Eils Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University and BioQuant Center, 69120, Heidelberg, Germany David T. W. Jones Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Peter Lichter German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany Lukas Chavez Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Marc Zapatka Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany Institute of Computer Science, Freie Universität Berlin, Berlin, Germany Stefan M. Pfister Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany ICGC PedBrain-Seq Project Peter Lichter Ursula Weber Roland Eils Andrey Korshunov Olaf Witt Stefan Pfister Guido Reifenberger Jörg Felsberg Christof von Kalle Manfred Schmidt Cynthia Bartholomä Michael Taylor Stefan Pfister David Jones Peter Lichter Natalie Jäger Ivo Buchhalter Jan Korbel Adrian Stütz Tobias Rausch Bernhard Radlwimmer Marie-Laure Yaspo Hans Lehrach Hans-Jörg Warnatz Pablo Landgraf Arndt Borkhardt Benedikt Brors Marc Zapatka Roland Eils Roland Eils Jürgen Eils Christian Lawerenz ICGC MMML-Seq Project Reiner Siebert Susanne Wagner Andrea Haake Julia Richter Gesine Richter Roland Eils Chris Lawerenz Jürgen Eils Jules Kerssemakers Christina Jaeger-Schmidt Ingrid Scholz Anke K. Bergmann Christoph Borst Birgit Burkhardt Alexander Claviez Martin Dreyling Sonja Eberth Hermann Einsele Norbert Frickhofen Siegfried Haas Martin-Leo Hansmann Dennis Karsch Michael Kneba Jasmin Lisfeld Luisa Mantovani-Löffler Marius Rohde German Ott Christina Stadler Peter Staib Stephan Stilgenbauer Lorenz Trümper Thorsten Zenz Martin-Leo Hansmann Dieter Kube Ralf Küppers Marc Weniger Michael Hummel Wolfram Klapper Ulrike Kostezka Dido Lenze Peter Möller Andreas Rosenwald German Ott Monika Szczepanowski Ole Ammerpohl Sietse M. Aukema Vera Binder Arndt Borkhardt Andrea Haake Jessica I. Hoell Ellen Leich Peter Lichter Cristina López Inga Nagel Jordan Pischimariov Bernhard Radlwimmer Julia Richter Philip Rosenstiel Andreas Rosenwald Markus Schilhabel Stefan Schreiber Inga Vater Rabea Wagener Reiner Siebert Stephan H. Bernhart Hans Binder Benedikt Brors Gero Doose Roland Eils Steve Hoffmann Lydia Hopp Daniel Hübschmann Kortine Kleinheinz Helene Kretzmer Markus Kreuz Jan Korbel David Langenberger Markus Loeffler Maciej Rosolowski Matthias Schlesner Peter F. Stadler Stephanie Sungalee nature25480 10.1038/nature25480 2017 02 05 2017 12 24 2018 February 28 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.
ASJC Scopus subject areas
- General
