Journal Article

The landscape of genomic alterations across childhood cancers

Weber, Ursula D., Liu, Yanling, Sturm, Dominik, Lohmann, Dietmar, Koster, Jan, Buchhalter, Ivo, Koscielniak, Ewa, Bender, Sebastian, Lambo, Sander, Hutter, Barbara, Richter, Günther H., Nathrath, Michaela, Wolf, Stephan, Northcott, Paul A., Rutkowski, Stefan, Kirschner-Schwabe, Renate, Eckert, Cornelia, Witt, Olaf, Eils, Roland, Molenaar, Jan J., Rudneva, Vasilisa A., Kontny, Udo, Kappler, Roland, Siebert, Reiner, Pfister, Stefan M., Resnick, Adam C., Dirksen, Uta, Zhou, Xin, Wegert, Jenny, Zapatka, Marc, Kleinheinz, Kortine, Burdach, Stefan, van Tilburg, Cornelis M., Pfaff, Elke, Fleischhack, Gudrun, Waanders, Angela J., Segura-Wang, Maia, Pajtler, Kristian W., Korbel, Jan O., Gessler, Manfred, Hübschmann, Daniel, Chavez, Lukas, Heinold, Michael, Kuhlen, Michaela, Westermann, Frank, Zhang, Jinghui, Johann, Pascal D., Brabetz, Sebastian, Schulte, Johannes, Zipprich, Gideon, Eggert, Angelika, Klingebiel, Thomas, Raman, Pichai, von Hoff, Katja, Schlesner, Matthias, Hettmer, Simone, Weischenfeldt, Joachim, Erkek, Serap, Piro, Rosario M., Baumhoer, Daniel, Frühwald, Michael, Jones, David T. W., Blattmann, Claud

2018

Overview

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. Analyses of genomes from 914 children, adolescents, and young adults provide a comprehensive resource of genomic alterations across a spectrum of common childhood cancers. Genomic landscape of childhood cancers The genetic alterations that give rise to childhood cancer are less well studied than those that give rise to adult cancers. Two papers in this issue report some of the first pan-cancer analyses of childhood cancers. Stefan Pfister and colleagues studied germline and somatic genomes from 914 young cancer patients, including children, adolescents and young adults. The tumour samples comprised 24 distinct molecular cancer types, including the most frequent and clinically relevant childhood cancers. The team characterized somatic mutation frequencies, genomic alterations, including structural variations and copy-number analysis, and mutational signatures. They found signatures associated with deficiencies of double-stranded break repair across all cancer types. Additionally, 7.6% of patients carried a likely pathogenic germline variant in a candidate cancer predisposition gene. Jinghui Zhang and colleagues analysed the genomes, exomes and transcriptomes of 1,699 paediatric leukaemias and solid tumours. They identified 142 driver genes in paediatric cancers, over half of which were specific to a single histotype. They also characterized copy number alterations and structural variation and identified 11 mutational signatures. Together, these papers provide a comprehensive resource for genomic alterations across common paediatric tumours, and highlight differences compared with the genomic alterations seen in adult cancers.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 49/23 / 631/208/69 / 631/67/2332 / 692/308/575 / 692/420/755 / 692/53/2423 / Adolescent / Adolescents / Adult / Adults / Bioinformatics / Cancer / Cancer research / Child / Childhood / Childhood cancer / Children / Chromothripsis / Clinical trials / Cohort Studies / Diploidy / DNA Copy Number Variations - genetics / Gene mutation / Genes / Genetic analysis / Genetic aspects / Genetic Predisposition to Disease - genetics / Genome, Human - genetics / Genomes / Genomics / Germ-Line Mutation - genetics / Health aspects / Humanities and Social Sciences / Humans / Life Sciences / Medical research / Molecular Targeted Therapy / multidisciplinary / Mutation / Mutation - genetics / Mutation Rate / Neoplasms / Neoplasms - classification / Neoplasms - drug therapy / Neoplasms - genetics / p53 Protein / Science / Signatures / Studies / Tumor Suppressor Protein p53 - genetics / Tumors / Workflow / Young Adult / Young adults