海德堡霍普儿童癌症中心Marc Zuckermann课题组对全球小鼠甲基组图谱的研究揭示了儿童癌症模型中亚型特异性拷贝数的改变。相关论文于2025年12月11日发表在《自然—遗传学》杂志上。

在这里，该研究组生成了31种儿童肿瘤类型的106种遗传母主题模型的全基因组DNA甲基化和CNA图谱，包括18种儿童胶质瘤的新模型。课题组证明了它们与人类疾病对应物的表观遗传相似性，并确定了实体特异性免疫浸润模式。课题组发现，小鼠肿瘤具有高度复发的CNA特征，这些特征明显基于肿瘤亚群和驱动癌基因，并表明这些CNA与匹配的人类肿瘤类型共享同质区域，从而揭示了在亚群特异性肿瘤发生中保守但以前未被充分认识的作用，可以通过提出的模型进行分析。他们的研究为儿童实体癌的全球可用小鼠模型提供了见解，并使功能性CNA询问成为可能，具有解锁儿童癌症新转化靶点的潜力。

据了解，拷贝数改变（CNAs）是癌症的标志，但由于技术限制和缺少模型系统，对其致癌作用的研究一直受到阻碍。

附：英文原文

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

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

Issue&Volume: 2025-12-11

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.

DOI: 10.1038/s41588-025-02419-4

Source: https://www.nature.com/articles/s41588-025-02419-4