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Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model |
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| Authors: | Theresa M Thole Joern Toedling Annika Sprüssel Sebastian Pfeil Larissa Savelyeva David Capper Clemens Messerschmidt Dieter Beule Stefanie Groeneveld-Krentz Cornelia Eckert Guido Gambara Anton G Henssen Sabine Finkler Johannes H Schulte Anja Sieber Nils Bluethgen Christian R A Regenbrecht Annette Künkele Marco Lodrini Angelika Eggert Hedwig E Deubzer |
| Institution: | 1. Department of Pediatric Hematology and Oncology, Charité - Universitätsmedizin Berlin, Berlin, Germany;2. Research Group Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany;3. Department of Neuropathology, Charité – Universitätsmedizin Berlin, Berlin, Germany;4. Core Unit Bioinformatics, Berliner Institut für Gesundheitsforschung (BIH), Berlin, Germany;5. CELLPhenomics GmbH, Berlin, Germany
Charité Comprehensive Cancer Center (CCCC), Charité - Universitätsmedizin Berlin, Berlin, Germany German Cancer Consortium (DKTK), Berlin, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany;6. Department of Pediatric Hematology and Oncology, Charité - Universitätsmedizin Berlin, Berlin, Germany Berliner Institut für Gesundheitsforschung (BIH), Berlin, Germany;7. Department of Pediatric Hematology and Oncology, Charité - Universitätsmedizin Berlin, Berlin, Germany German Cancer Consortium (DKTK), Berlin, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany Berliner Institut für Gesundheitsforschung (BIH), Berlin, Germany;8. Computational Modelling in Medicine, Charité – Universitätsmedizin Berlin, Institute for Pathology, Berlin, Germany IRI Life Sciences, Humboldt University Berlin, Berlin, Germany;9. Berliner Institut für Gesundheitsforschung (BIH), Berlin, Germany Computational Modelling in Medicine, Charité – Universitätsmedizin Berlin, Institute for Pathology, Berlin, Germany IRI Life Sciences, Humboldt University Berlin, Berlin, Germany;10. CELLPhenomics GmbH, Berlin, Germany Department for Pathology, Medical Faculty, Otto-von-Guericke University of Magdeburg, Magdeburg, Germany |
| Abstract: | Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system. |
| Keywords: | embryonal tumor single-nucleotide variant analysis copy number variation analysis clonal reconstruction MYCN amplification preclinical drug testing |