Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts
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Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts. / Pöschl, Julia; Stark, Sebastian; Neumann, Philipp; Gröbner, Susanne; Kawauchi, Daisuke; Jones, David T W; Northcott, Paul A; Lichter, Peter; Pfister, Stefan M; Kool, Marcel; Schüller, Ulrich.
in: ACTA NEUROPATHOL, Jahrgang 128, Nr. 1, 07.2014, S. 123-36.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts
AU - Pöschl, Julia
AU - Stark, Sebastian
AU - Neumann, Philipp
AU - Gröbner, Susanne
AU - Kawauchi, Daisuke
AU - Jones, David T W
AU - Northcott, Paul A
AU - Lichter, Peter
AU - Pfister, Stefan M
AU - Kool, Marcel
AU - Schüller, Ulrich
PY - 2014/7
Y1 - 2014/7
N2 - 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.
AB - 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.
KW - Adult
KW - Age Factors
KW - Animals
KW - Brain
KW - Brain Neoplasms
KW - Disease Models, Animal
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Neoplastic
KW - Genomics
KW - Hedgehog Proteins
KW - Humans
KW - Infant
KW - Medulloblastoma
KW - Mice
KW - Mice, Transgenic
KW - Mutation
KW - Polymorphism, Single Nucleotide
KW - Receptors, Cell Surface
KW - Signal Transduction
KW - Transcriptome
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1007/s00401-014-1297-8
DO - 10.1007/s00401-014-1297-8
M3 - SCORING: Journal article
C2 - 24871706
VL - 128
SP - 123
EP - 136
JO - ACTA NEUROPATHOL
JF - ACTA NEUROPATHOL
SN - 0001-6322
IS - 1
ER -