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Int J Cancer. 2020 Feb 15;146(4):1031-1041. doi: 10.1002/ijc.32572. Epub 2019 Aug 1.

Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model.

Author information

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.
6
Charité Comprehensive Cancer Center (CCCC), Charité - Universitätsmedizin Berlin, Berlin, Germany.
7
German Cancer Consortium (DKTK), Berlin, Germany.
8
German Cancer Research Center (DKFZ), Heidelberg, Germany.
9
Berliner Institut für Gesundheitsforschung (BIH), Berlin, Germany.
10
Computational Modelling in Medicine, Charité - Universitätsmedizin Berlin, Institute for Pathology, Berlin, Germany.
11
IRI Life Sciences, Humboldt University Berlin, Berlin, Germany.
12
Department for Pathology, Medical Faculty, Otto-von-Guericke University of Magdeburg, Magdeburg, Germany.
13
Neuroblastoma Research Group, Experimental and Clinical Research Center (ECRC) of the Charité and the Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, 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:

MYCN amplification; clonal reconstruction; copy number variation analysis; embryonal tumor; preclinical drug testing; single-nucleotide variant analysis

PMID:
31304977
DOI:
10.1002/ijc.32572
[Indexed for MEDLINE]

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