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Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts

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Abstract

Medulloblastoma is a malignant embryonal brain tumor with highly variable outcome. In order to study the biology of this tumor and to perform preclinical treatment studies, a lot of effort has been put into the generation of appropriate mouse models. The usage of these models, however, has become debatable with the advances in human medulloblastoma subgrouping. This study brings together multiple relevant mouse models and matches genetic alterations and gene expression data of 140 murine tumors with 423 human medulloblastomas in a global way. Using AGDEX analysis and k-means clustering, we show that the Blbp-cre::Ctnnb1(ex3)Fl/+ Trp53 Fl/Fl mouse model fits well to human WNT medulloblastoma, and that, among various Myc- or Mycn-based mouse medulloblastomas, tumors in Glt1-tTA::TRE-MYCN/Luc mice proved to be most specific for human group 3 medulloblastoma. None of the analyzed models displayed a significant match to group 4 tumors. Intriguingly, mice with Ptch1 or Smo mutations selectively modeled SHH medulloblastomas of adulthood, although such mutations occur in all human age groups. We therefore suggest that the infantile or adult gene expression pattern of SHH MBs are not solely determined by specific mutations. This is supported by the observation that human medulloblastomas with PTCH1 mutations displayed more similarities to PTCH1 wild-type tumors of the same age group than to PTCH1-mutated tumors of the other age group. Together, we provide novel insights into previously unrecognized specificity of distinct models and suggest these findings as a solid basis to choose the appropriate model for preclinical studies on medulloblastoma.

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Acknowledgments

We thank Dr. Y. Lee and Dr. P. McKinnon (both Memphis, TN, USA) for providing microarray data. We are further indebted to Dr. Dr. M. Dorostkar (Munich, Germany) and all members of the Schüller group for very fruitful discussions. This work was supported by grants from the Deutsche Krebshilfe (Max-Eder junior research program to U.S.), the Wilhelm Sander Foundation (to U.S.), the Else-Kröner-Fresenius Foundation (to U.S.) and the Friedrich Baur Foundation (to J. P.).

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Authors and Affiliations

  1. Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Feodor-Lynen-Strasse 23, 81377, Munich, Germany

    Julia Pöschl & Ulrich Schüller

  2. Division of Pediatric Neuroncology (B062), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Sebastian Stark, Susanne Gröbner, Daisuke Kawauchi, David T. W. Jones, Paul A. Northcott, Stefan M. Pfister & Marcel Kool

  3. Department of Informatics, Technical University, Munich, Germany

    Philipp Neumann

  4. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Peter Lichter

  5. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

    Stefan M. Pfister

  6. Department of General Pediatrics, Heidelberg University Hospital, Heidelberg, Germany

    Sebastian Stark

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  1. Julia Pöschl
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  2. Sebastian Stark
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  3. Philipp Neumann
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  10. Marcel Kool
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Correspondence to Ulrich Schüller.

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M. Kool and U. Schüller are co-senior authors.

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Pöschl, J., Stark, S., Neumann, P. et al. Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts. Acta Neuropathol 128, 123–136 (2014). https://doi.org/10.1007/s00401-014-1297-8

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  • DOI: https://doi.org/10.1007/s00401-014-1297-8

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