A biobank of patient-derived pediatric brain tumor models

Brabetz, Sebastian; Leary, Sarah; Gröbner, Susanne; Nakamoto, Madison W.; Şeker-Cin, Huriye; Girard, Emily J.; Cole, Bonnie; Strand, Andrew D.; Bloom, Karina; Hovestadt, Volker; Mack, Norman; Pakiam, Fiona; Schwalm, Benjamin; Korshunov, Andrey; Balasubramanian, Gnana Prakash; Northcott, Paul A.; Pedro, Kyle D.; Dey, Joyoti; Hansen, Stacey; Ditzler, Sally; Lichter, Peter; Chávez, Lukas; Jones, David; Koster, Jan; Pfister, Stefan M.; Kool, Marcel; Olson, James M.

doi:10.1038/s41591-018-0207-3

Cited by 133 publications

(147 citation statements)

References 65 publications

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“…Future banking strategies for patients with OS undergoing surgical resections or biopsies should recognize the potential value of well-annotated, properly handled and preserved samples that are sufficient for performing global analyses. 20…”

Section: Feasibilitymentioning

confidence: 99%

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

Roberts

Lizardo

Reed

et al. 2019

Cancer

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Patients who are diagnosed with osteosarcoma (OS) today receive the same therapy that patients have received over the last 4 decades. Extensive efforts to identify more effective or less toxic regimens have proved disappointing. As we enter a postgenomic era in which we now recognize OS not as a cancer of mutations but as one defined by p53 loss, chromosomal complexity, copy number alteration, and profound heterogeneity, emerging threads of discovery leave many hopeful that an improving understanding of biology will drive discoveries that improve clinical care. Under the organization of the Bone Tumor Biology Committee of the Children's Oncology Group, a team of clinicians and scientists sought to define the state of the science and to identify questions that, if answered, have the greatest potential to drive fundamental clinical advances. Having discussed these questions in a series of meetings, each led by invited experts, we distilled these conversations into a series of seven Provocative Questions. These include questions about the molecular events that trigger oncogenesis, the genomic and epigenomic drivers of disease, the biology of lung metastasis, research models that best predict clinical outcomes, and processes for translating findings into clinical trials. Here, we briefly present each Provocative Question, review the current scientific evidence, note the immediate opportunities, and speculate on the impact that answered questions might have on the field. We do so with an intent to provide a framework around which investigators can build programs and collaborations to tackle the hardest problems and to establish research priorities for those developing policies and providing funding. Cancer 2019;125:3514-3525.

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Section: Feasibilitymentioning

confidence: 99%

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

Roberts

Lizardo

Reed

et al. 2019

Cancer

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“…Orthotopically xenografting patient samples may present an interesting alternative approach. Recently, orthotopically implanted patient‐derived neuroblastoma and medulloblastoma xenografts were reported to maintain genetic, epigenetic, transcriptional and phenotypic stability and reflect aspects of spatial intratumor heterogeneity . Generating (orthotopic) neuroblastoma patient‐derived xenografts in mice is very useful, but does not support high‐throughput screening and continues to be inefficient, despite the use of the most recent implantation strategies, for a subset of neuroblastomas that include tumors lacking MYCN amplifications or TERT alterations.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, orthotopically implanted patient-derived neuroblastoma and medulloblastoma xenografts were reported to maintain genetic, epigenetic, transcriptional and phenotypic stability and reflect aspects of spatial intratumor heterogeneity. 38,39 Generating (orthotopic) neuroblastoma patientderived xenografts in mice is very useful, but does not support high-throughput screening and continues to be inefficient, despite the use of the most recent implantation strategies, for a subset of neuroblastomas that include tumors lacking MYCN amplifications or TERT alterations. Establishing neuroblastoma organoids from fresh samples may, therefore, represent a third preclinical neuroblastoma model, situated between the in vitro 2D cell lines and the in vivo PDX models.…”

Section: Discussionmentioning

confidence: 99%

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

Thole

Toedling

Sprüssel

et al. 2019

Intl Journal of Cancer

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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.

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“…The same concept applies to pHGG models including cellular cultures, patient derived xenografts or murine models. 30 Each has their unique advantages and limitations, but integration is essential to drive the field forward and necessary for cross-validation studies.…”

Section: Discussionmentioning

confidence: 99%

Pediatric High Grade Glioma Resources From the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pediatric Brain Tumor Atlas (PBTA)

Ijaz

Koptyra

Gaonkar

et al. 2019

Preprint

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Background: Pediatric high grade glioma (pHGG) remains a fatal disease. Increased access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Children's Brain Tumor Tissue Consortium (CBTTC) from the first release (October 2018) of the Pediatric Brain Tumor Atlas (PBTA).Methods: pHGG tumors with associated clinical data and imaging were prospectively collected through the CBTTC and analyzed as the Pediatric Brain Tumor Atlas (PBTA) with processed genomic data deposited into PedcBioPortal for broad access and visualization. Matched tumor was cultured to create high grade glioma cell lines analyzed by targeted and WGS and RNA-seq. A tissue microarray (TMA) of primary pHGG tumors was also created. Results:The pHGG set included 87 collection events (73 patients, 60% at diagnosis, median age of 9 yrs, 55% female, 46% hemispheric). Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36% H3.3, 47% TP53, 24% ATRX and 7% BRAF V600E variants). A pHGG TMA (n=77), includes 36 (53%) patient tumors with matched sequencing. At least one established glioma cell line was generated from 23 patients (32%). Unique reagents include those derived from a H3.3 G34R glioma and from tumors with mismatch repair deficiency. Conclusion:The CBTTC and PBTA have created an openly available integrated resource of over 2,000 tumors, including a rich set of pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.

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A biobank of patient-derived pediatric brain tumor models

Cited by 133 publications

References 65 publications

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

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

Pediatric High Grade Glioma Resources From the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pediatric Brain Tumor Atlas (PBTA)

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