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@INPROCEEDINGS{Gopisetty:294425,
      author       = {A. Gopisetty and A. Federico and D. Surdez and Y. Iddir and
                      S. Zaidi and A. Saint-Charles and J. Waterfall and E.
                      Saberi-Ansari and J. Wierzbinska and A. Schlicker and N.
                      Mack and B. Schwalm and C. Previti and L. Weiser and I.
                      Buchhalter and A.-L. Böttcher and M. Sill and R. Autry and
                      F. Estermann and D. Jones and R. Volckmann and D.
                      Zwijnenburg and A. Eggert and O. Heidenreich and F. Iradier
                      and I. Jeremias and H. Kovar and J.-H. Klusmann and K.-M.
                      Debatin and S. Bomken and P. Hamerlik and M. Hattersley and
                      O. Witt and L. Chesler and A. Mackay and J. Gojo and S.
                      Cairo and J. Schueler and J. Schulte and B. Geoerger and J.
                      J. Molenaar and D. J. Shields and H. N. Caron and G. Vassal
                      and L. F. Stancato and S. M. Pfister and N. Jaeger and J.
                      Koster and M. Kool and G. Schleiermacher},
      title        = {{A}bstract 234: {ITCC}-{P}4: {G}enomic profiling and
                      analyses of pediatric patient tumor and patient-derived
                      xenograft ({PDX}) models for high throughput in vivo
                      testing},
      issn         = {1538-7445},
      reportid     = {DKFZ-2024-02254},
      year         = {2023},
      abstract     = {Advancements in state-of-the-art molecular profiling
                      techniques have resulted in better understanding of
                      pediatric cancers and driver events. It has become apparent
                      that pediatric cancers are significantly more heterogeneous
                      than previously thought as evidenced by the number of novel
                      entities and subtypes that have been identified with
                      distinct molecular and clinical characteristics. For most of
                      these newly recognized entities there are extremely limited
                      treatment options available. The ITCC-P4 consortium is an
                      international collaboration between several European
                      academic centers and pharmaceutical companies, with the
                      overall aim to establish a sustainable platform of >400
                      molecularly well-characterized PDX models of high-risk
                      pediatric cancers, their tumors and matching controls and to
                      use the PDX models for in vivo testing of novel
                      mechanism-of-action based treatments. Currently, 251 models
                      are fully characterized, including 182 brain and 69
                      non-brain PDX models, representing 112 primary models, 92
                      relapse, 42 metastasis and 4 progressions under treatment
                      models. Using low coverage whole-genome and whole exome
                      sequencing, somatic mutation calling, DNA copy number and
                      methylation analysis we aim to define genetic features in
                      our PDX models and estimate the molecular fidelity of PDX
                      models compared to their patient tumor. Based on DNA
                      methylation profiling we identified 43 different tumor
                      subgroups within 18 cancer entities. Mutational landscape
                      analysis identified key somatic and germline oncogenic
                      drivers. Ependymoma PDX models displayed the C11orf95-RELA
                      fusion event, YAP1, C11orf95 and RELA structural variants.
                      Medulloblastoma models were driven by MYCN, TP53, GLI2, SUFU
                      and PTEN. High-grade glioma samples showed TP53, ATRX, MYCN
                      and PIK3CA somatic SNVs, along with focal deletions in
                      CDKN2A in chromosome 9. Neuroblastoma models were enriched
                      for ALK SNVs and/or MYCN focal amplification, ATRX SNVs and
                      CDKN2A/B deletions. Tumor mutational burden across entities
                      and copy number analysis was performed to identify
                      allele-specific copy number detection in tumor-normal pairs.
                      Large chromosomal aberrations (deletions, duplications)
                      detected in the PDX models were concurrent with molecular
                      alterations frequently observed in each tumor type
                      -isochromosome 17 was detected in 5 medulloblastoma models,
                      while deletion of chromosome arm 1p or gain of parts of 17q
                      in neuroblastomas which correlate with tumor progression. We
                      observe clonal evolution of somatic variants not only in
                      certain PDX-tumor pairs but also between disease states. The
                      multi-omics approach in this study provides insight into the
                      mutational landscape and patterns of the PDX models thus
                      providing an overview of molecular mechanisms facilitating
                      the identification and prioritization of oncogenic drivers
                      and potential biomarkers for optimal treatment therapies.},
      ddc          = {610},
      typ          = {PUB:(DE-HGF)1},
      doi          = {10.1158/1538-7445.AM2023-234},
      url          = {https://inrepo02.dkfz.de/record/294425},
}