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; Marc Zapatka; 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; Stefan M. Pfister

doi:10.1038/nature25480

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 ErkekSander 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, Marc Zapatka, 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, Stefan M. Pfister

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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
Pages (from-to)	321-327
Number of pages	7
Journal	Nature
Volume	555
Issue number	7696
DOIs	https://doi.org/10.1038/nature25480
Publication status	Published - 15 Mar 2018
Externally published	Yes

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Gröbner, S. N., Worst, B. C., Weischenfeldt, J., Buchhalter, I., Kleinheinz, K., Rudneva, V. A., Johann, P. D., Balasubramanian, G. P., Segura-Wang, M., Brabetz, S., Bender, S., Hutter, B., Sturm, D., Pfaff, E., Hübschmann, D., Zipprich, G., Heinold, M., Eils, J., Lawerenz, C., ... Pfister, S. M. (2018). The landscape of genomic alterations across childhood cancers. Nature, 555(7696), 321-327. https://doi.org/10.1038/nature25480

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title = "The landscape of genomic alterations across childhood cancers",

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.",

author = "Gr{\"o}bner, {Susanne N.} and Worst, {Barbara C.} and Joachim Weischenfeldt and Ivo Buchhalter and Kortine Kleinheinz and Rudneva, {Vasilisa A.} and Johann, {Pascal D.} and Balasubramanian, {Gnana Prakash} and Maia Segura-Wang and Sebastian Brabetz and Sebastian Bender and Barbara Hutter and Dominik Sturm and Elke Pfaff and Daniel H{\"u}bschmann and Gideon Zipprich and Michael Heinold and J{\"u}rgen Eils and Christian Lawerenz and Serap Erkek and Sander Lambo and Sebastian Waszak and Claudia Blattmann and Arndt Borkhardt and Michaela Kuhlen and Angelika Eggert and Simone Fulda and Manfred Gessler and Jenny Wegert and Roland Kappler and Daniel Baumhoer and Stefan Burdach and Renate Kirschner-Schwabe and Udo Kontny and Kulozik, {Andreas E.} and Dietmar Lohmann and Simone Hettmer and Cornelia Eckert and Stefan Bielack and Michaela Nathrath and Charlotte Niemeyer and Richter, {G{\"u}nther H.} and Johannes Schulte and Reiner Siebert and Frank Westermann and Molenaar, {Jan J.} and Gilles Vassal and Hendrik Witt and Marc Zapatka and Birgit Burkhardt and Kratz, {Christian P.} and Olaf Witt and Tilburg, {Cornelis M.Van} and Kramm, {Christof M.} and Gudrun Fleischhack and Uta Dirksen and Stefan Rutkowski and Michael Fr{\"u}hwald and Hoff, {Katja Von} and Stephan Wolf and Thomas Klingebiel and Ewa Koscielniak and Pablo Landgraf and Jan Koster and Resnick, {Adam C.} and Jinghui Zhang and Yanling Liu and Xin Zhou and Waanders, {Angela J.} and Zwijnenburg, {Danny A.} and Pichai Raman and Benedikt Brors and Weber, {Ursula D.} and Northcott, {Paul A.} and Pajtler, {Kristian W.} and Marcel Kool and Piro, {Rosario M.} and Korbel, {Jan O.} and Matthias Schlesner and Roland Eils and Jones, {David T.W.} and Peter Lichter and Lukas Chavez and Pfister, {Stefan M.}",

year = "2018",

month = mar,

day = "15",

doi = "10.1038/nature25480",

language = "English",

volume = "555",

pages = "321--327",

journal = "Nature",

issn = "0028-0836",

number = "7696",

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Gröbner, SN, Worst, BC, Weischenfeldt, J, Buchhalter, I, Kleinheinz, K, Rudneva, VA, Johann, PD, Balasubramanian, GP, Segura-Wang, M, Brabetz, S, Bender, S, Hutter, B, Sturm, D, Pfaff, E, Hübschmann, D, Zipprich, G, Heinold, M, Eils, J, Lawerenz, C, Erkek, S, Lambo, S, Waszak, S, Blattmann, C, Borkhardt, A, Kuhlen, M, Eggert, A, Fulda, S, Gessler, M, Wegert, J, Kappler, R, Baumhoer, D, Burdach, S, Kirschner-Schwabe, R, Kontny, U, Kulozik, AE, Lohmann, D, Hettmer, S, Eckert, C, Bielack, S, Nathrath, M, Niemeyer, C, Richter, GH, Schulte, J, Siebert, R, Westermann, F, Molenaar, JJ, Vassal, G, Witt, H, Zapatka, M, Burkhardt, B, Kratz, CP, Witt, O, Tilburg, CMV, Kramm, CM, Fleischhack, G, Dirksen, U, Rutkowski, S, Frühwald, M, Hoff, KV, Wolf, S, Klingebiel, T, Koscielniak, E, Landgraf, P, Koster, J, Resnick, AC, Zhang, J, Liu, Y, Zhou, X, Waanders, AJ, Zwijnenburg, DA, Raman, P, Brors, B, Weber, UD, Northcott, PA, Pajtler, KW, Kool, M, Piro, RM, Korbel, JO, Schlesner, M, Eils, R, Jones, DTW, Lichter, P, Chavez, L & Pfister, SM 2018, 'The landscape of genomic alterations across childhood cancers', Nature, vol. 555, no. 7696, pp. 321-327. https://doi.org/10.1038/nature25480

TY - JOUR

T1 - The landscape of genomic alterations across childhood cancers

AU - Gröbner, Susanne N.

AU - Worst, Barbara C.

AU - Weischenfeldt, Joachim

AU - Buchhalter, Ivo

AU - Kleinheinz, Kortine

AU - Rudneva, Vasilisa A.

AU - Johann, Pascal D.

AU - Balasubramanian, Gnana Prakash

AU - Segura-Wang, Maia

AU - Brabetz, Sebastian

AU - Bender, Sebastian

AU - Hutter, Barbara

AU - Sturm, Dominik

AU - Pfaff, Elke

AU - Hübschmann, Daniel

AU - Zipprich, Gideon

AU - Heinold, Michael

AU - Eils, Jürgen

AU - Lawerenz, Christian

AU - Erkek, Serap

AU - Lambo, Sander

AU - Waszak, Sebastian

AU - Blattmann, Claudia

AU - Borkhardt, Arndt

AU - Kuhlen, Michaela

AU - Eggert, Angelika

AU - Fulda, Simone

AU - Gessler, Manfred

AU - Wegert, Jenny

AU - Kappler, Roland

AU - Baumhoer, Daniel

AU - Burdach, Stefan

AU - Kirschner-Schwabe, Renate

AU - Kontny, Udo

AU - Kulozik, Andreas E.

AU - Lohmann, Dietmar

AU - Hettmer, Simone

AU - Eckert, Cornelia

AU - Bielack, Stefan

AU - Nathrath, Michaela

AU - Niemeyer, Charlotte

AU - Richter, Günther H.

AU - Schulte, Johannes

AU - Siebert, Reiner

AU - Westermann, Frank

AU - Molenaar, Jan J.

AU - Vassal, Gilles

AU - Witt, Hendrik

AU - Zapatka, Marc

AU - Burkhardt, Birgit

AU - Kratz, Christian P.

AU - Witt, Olaf

AU - Tilburg, Cornelis M.Van

AU - Kramm, Christof M.

AU - Fleischhack, Gudrun

AU - Dirksen, Uta

AU - Rutkowski, Stefan

AU - Frühwald, Michael

AU - Hoff, Katja Von

AU - Wolf, Stephan

AU - Klingebiel, Thomas

AU - Koscielniak, Ewa

AU - Landgraf, Pablo

AU - Koster, Jan

AU - Resnick, Adam C.

AU - Zhang, Jinghui

AU - Liu, Yanling

AU - Zhou, Xin

AU - Waanders, Angela J.

AU - Zwijnenburg, Danny A.

AU - Raman, Pichai

AU - Brors, Benedikt

AU - Weber, Ursula D.

AU - Northcott, Paul A.

AU - Pajtler, Kristian W.

AU - Kool, Marcel

AU - Piro, Rosario M.

AU - Korbel, Jan O.

AU - Schlesner, Matthias

AU - Eils, Roland

AU - Jones, David T.W.

AU - Lichter, Peter

AU - Chavez, Lukas

AU - Pfister, Stefan M.

PY - 2018/3/15

Y1 - 2018/3/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85044244244&partnerID=8YFLogxK

U2 - 10.1038/nature25480

DO - 10.1038/nature25480

M3 - Article

C2 - 29489754

AN - SCOPUS:85044244244

SN - 0028-0836

VL - 555

SP - 321

EP - 327

JO - Nature

JF - Nature

IS - 7696

ER -

The landscape of genomic alterations across childhood cancers

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