Investigation of a global mouse methylome atlas reveals subtype-specific copy number alterations in pediatric cancer models

Copy number alterations (CNAs) are hallmarks of cancer, yet investigation of their oncogenic role has been hindered by technical limitations and missing model systems. Here we generated a genome-wide DNA methylation and CNA atlas of 106 genetic mouse models across 31 pediatric tumor types, including 18 new models for pediatric glioma. We demonstrated their epigenetic resemblance to human disease counterparts and identified entity-specific patterns of immune infiltration. We discovered that mouse tumors harbor highly recurrent CNA signatures that occur distinctly based on the tumor subgroup and driving oncogene and showed that these CNAs share syntenic regions with the matching human tumor types, thereby revealing a conserved but previously underappreciated role in subgroup-specific tumorigenesis that can be analyzed using the presented models. Our study provides insights into globally available mouse models for pediatric solid cancers and enables access to functional CNA interrogation, with the potential to unlock new translational targets in pediatric cancers.

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Publication Details

Journal
Nature Genetics
Published
2025-12-11
DOI
https://doi.org/10.1038/s41588-025-02419-4
Citations
2
Primary Topic
Neuroblastoma Research and Treatments
Type
article
Field-Weighted Citation Impact
2.78
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article

Investigation of a global mouse methylome atlas reveals subtype-specific copy number alterations in pediatric cancer models

Matthias Dottermusch, Lena M. Kutscher, Nina Hofmann, Kristian W. Pajtler et al.
2 citations
Nature Genetics
Neuroblastoma Research and Treatments
2.78
article

Investigation of a global mouse methylome atlas reveals subtype-specific copy number alterations in pediatric cancer models

Matthias Dottermusch, Lena M. Kutscher, Nina Hofmann, Kristian W. Pajtler, Franck Bourdeaut, Yanxin Pei, Olivier Ayrault, Rajanya Roy, Rainer Glaß, Ana Guerreiro Stücklin, Jessica Taylor, Roland Imle, Dominik Sturm, Kati Ernst, Lea Altendorf, Julia E. Neumann, Jiying Cheng, Melanie Schoof, Tuyu Zheng, Simon Haas, Kornelius Kerl, Michael Spohn, Stefan M. Pfister, Paul A. Northcott, Carolin Göbel, Levke-Sophie Peter, Tim Holland‐Letz, Alaide Morcavallo, Marc Zuckermann, Ana Banito, Louis Chesler, Haotian Zhao, Daisuke Kawauchi, Fredrik J. Swartling, Ulrich Schüller, Judith Niesen, Andreas Postlmayr, William A. Weiss, Dominik Vonficht, Viveka Nand Yadav, Zhi‐Yan Han, Richard J. Gilbertson, Gerrit Wolters‐Eisfeld, Ryo Shiraishi, Najiba Murad, Martin Sill, Alessia Cais, David Jones, Monika Yadav, Martin A. Horstmann, Kenneth Chun‐Ho Chan, Wan-Chen Wang, A Fürst, Garrett R. Gibson
article en
2 citations

Abstract

Copy number alterations (CNAs) are hallmarks of cancer, yet investigation of their oncogenic role has been hindered by technical limitations and missing model systems. Here we generated a genome-wide DNA methylation and CNA atlas of 106 genetic mouse models across 31 pediatric tumor types, including 18 new models for pediatric glioma. We demonstrated their epigenetic resemblance to human disease counterparts and identified entity-specific patterns of immune infiltration. We discovered that mouse tumors harbor highly recurrent CNA signatures that occur distinctly based on the tumor subgroup and driving oncogene and showed that these CNAs share syntenic regions with the matching human tumor types, thereby revealing a conserved but previously underappreciated role in subgroup-specific tumorigenesis that can be analyzed using the presented models. Our study provides insights into globally available mouse models for pediatric solid cancers and enables access to functional CNA interrogation, with the potential to unlock new translational targets in pediatric cancers.

Nature GeneticsVol. 58(1)
Université Paris-Sud (FR), Uppsala University (SE), Centre National de la Recherche Scientifique (FR), St. Jude Children's Research Hospital (US), Children's National (US), Institute of Cancer Research (GB), Inserm (FR), Universität Hamburg (DE), German Cancer Research Center (DE), University of California, San Francisco (US), Max Delbrück Center (DE), Heidelberg University (DE), University of Cambridge (GB), Université Paris Sciences et Lettres (FR), Université Paris-Saclay (FR), Cancer Research UK (GB), University Hospital Heidelberg (DE), LMU Klinikum (DE), Cancer Research UK Cambridge Center (GB), The University of Kansas Cancer Center (US), University Hospital Münster (DE), National Center of Neurology and Psychiatry (JP), New York Institute of Technology (US), University Medical Center Hamburg-Eppendorf (DE), Kinderkrebs-Zentrum Hamburg (DE), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), Royal Marsden Hospital (GB), University Cancer Center Hamburg (DE), University Children's Hospital Zurich (CH), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Mercy Research (US), DKFZ-ZMBH Alliance (DE), Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE), UCSF Helen Diller Family Comprehensive Cancer Center (US), University of Missouri–Kansas City (US), Institut Curie (FR), Ludwig-Maximilians-Universität München (DE)
Openalex Percentile: Top 8%
Neuroblastoma Research and Treatments
2.78
DOIOpen Access PDFOpenAlex
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