The landscape of genomic alterations across childhood cancers

ICGC PedBrain-Seq Project

doi:10.1038/nature25480

The landscape of genomic alterations across childhood cancers

ICGC PedBrain-Seq Project

404 Citations (Scopus)

126 Downloads (Pure)

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
Journal	Nature
Volume	555
Issue number	7696
Pages (from-to)	321-327
Number of pages	7
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature25480
Publication status	Published - 15 Mar 2018

Keywords

Adolescent
Adult
Child
Chromothripsis
Cohort Studies
DNA Copy Number Variations/genetics
Diploidy
Genetic Predisposition to Disease/genetics
Genome, Human/genetics
Genomics
Germ-Line Mutation/genetics
Humans
Molecular Targeted Therapy
Mutation/genetics
Mutation Rate
Neoplasms/classification
Tumor Suppressor Protein p53/genetics
Young Adult

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/nature25480Licence: CC BY

nature25480Final published version, 7.79 MBLicence: CC BY

Cite this

@article{f645ada6f7c34565b427cbf7960f48e6,

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.",

keywords = "Adolescent, Adult, Child, Chromothripsis, Cohort Studies, DNA Copy Number Variations/genetics, Diploidy, Genetic Predisposition to Disease/genetics, Genome, Human/genetics, Genomics, Germ-Line Mutation/genetics, Humans, Molecular Targeted Therapy, Mutation/genetics, Mutation Rate, Neoplasms/classification, Tumor Suppressor Protein p53/genetics, Young Adult",

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 Birgit Burkhardt and Kratz, {Christian P} and {ICGC PedBrain-Seq Project}",

year = "2018",

month = mar,

day = "15",

doi = "10.1038/nature25480",

language = "English",

volume = "555",

pages = "321--327",

journal = "Nature",

issn = "0028-0836",

publisher = "nature publishing group",

number = "7696",

}

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 - Burkhardt, Birgit

AU - Kratz, Christian P

AU - ICGC PedBrain-Seq Project

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.

KW - Adolescent

KW - Adult

KW - Child

KW - Chromothripsis

KW - Cohort Studies

KW - DNA Copy Number Variations/genetics

KW - Diploidy

KW - Genetic Predisposition to Disease/genetics

KW - Genome, Human/genetics

KW - Genomics

KW - Germ-Line Mutation/genetics

KW - Humans

KW - Molecular Targeted Therapy

KW - Mutation/genetics

KW - Mutation Rate

KW - Neoplasms/classification

KW - Tumor Suppressor Protein p53/genetics

KW - Young Adult

U2 - 10.1038/nature25480

DO - 10.1038/nature25480

M3 - Journal article

C2 - 29489754

SN - 0028-0836

VL - 555

SP - 321

EP - 327

JO - Nature

JF - Nature

IS - 7696

ER -

The landscape of genomic alterations across childhood cancers

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this