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000294425 005__ 20241202094939.0
000294425 0247_ $$2doi$$a10.1158/1538-7445.AM2023-234
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000294425 0247_ $$2ISSN$$a0099-7374
000294425 0247_ $$2ISSN$$a0008-5472
000294425 0247_ $$2ISSN$$a1538-7445
000294425 037__ $$aDKFZ-2024-02254
000294425 082__ $$a610
000294425 1001_ $$aGopisetty, Apurva$$b0
000294425 245__ $$aAbstract 234: ITCC-P4: Genomic profiling and analyses of pediatric patient tumor and patient-derived xenograft (PDX) models for high throughput in vivo testing
000294425 260__ $$c2023
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000294425 520__ $$aAdvancements 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.
000294425 588__ $$aDataset connected to CrossRef, Journals: inrepo02.dkfz.de
000294425 7001_ $$aFederico, Aniello$$b1
000294425 7001_ $$aSurdez, Didier$$b2
000294425 7001_ $$aIddir, Yasmine$$b3
000294425 7001_ $$aZaidi, Sakina$$b4
000294425 7001_ $$aSaint-Charles, Alexandra$$b5
000294425 7001_ $$aWaterfall, Joshua$$b6
000294425 7001_ $$aSaberi-Ansari, Elnaz$$b7
000294425 7001_ $$aWierzbinska, Justyna$$b8
000294425 7001_ $$aSchlicker, Andreas$$b9
000294425 7001_ $$aMack, Norman$$b10
000294425 7001_ $$aSchwalm, Benjamin$$b11
000294425 7001_ $$aPreviti, Christopher$$b12
000294425 7001_ $$aWeiser, Lena$$b13
000294425 7001_ $$aBuchhalter, Ivo$$b14
000294425 7001_ $$aBöttcher, Anna-Lisa$$b15
000294425 7001_ $$aSill, Martin$$b16
000294425 7001_ $$aAutry, Robert$$b17
000294425 7001_ $$aEstermann, Frank$$b18
000294425 7001_ $$aJones, David$$b19
000294425 7001_ $$aVolckmann, Richard$$b20
000294425 7001_ $$aZwijnenburg, Danny$$b21
000294425 7001_ $$aEggert, Angelika$$b22
000294425 7001_ $$aHeidenreich, Olaf$$b23
000294425 7001_ $$aIradier, Fatima$$b24
000294425 7001_ $$aJeremias, Irmela$$b25
000294425 7001_ $$aKovar, Heinrich$$b26
000294425 7001_ $$aKlusmann, Jan-Henning$$b27
000294425 7001_ $$aDebatin, Klaus-Michael$$b28
000294425 7001_ $$aBomken, Simon$$b29
000294425 7001_ $$aHamerlik, Petra$$b30
000294425 7001_ $$aHattersley, Maureen$$b31
000294425 7001_ $$aWitt, Olaf$$b32
000294425 7001_ $$aChesler, Louis$$b33
000294425 7001_ $$aMackay, Alan$$b34
000294425 7001_ $$aGojo, Johannes$$b35
000294425 7001_ $$aCairo, Stefano$$b36
000294425 7001_ $$aSchueler, Julia$$b37
000294425 7001_ $$aSchulte, Johannes$$b38
000294425 7001_ $$aGeoerger, Birgit$$b39
000294425 7001_ $$aMolenaar, Jan J.$$b40
000294425 7001_ $$aShields, David J.$$b41
000294425 7001_ $$aCaron, Hubert N.$$b42
000294425 7001_ $$aVassal, Gilles$$b43
000294425 7001_ $$aStancato, Louis F.$$b44
000294425 7001_ $$aPfister, Stefan M.$$b45
000294425 7001_ $$aJaeger, Natalie$$b46
000294425 7001_ $$aKoster, Jan$$b47
000294425 7001_ $$aKool, Marcel$$b48
000294425 7001_ $$aSchleiermacher, Gudrun$$b49
000294425 773__ $$0PERI:(DE-600)2036785-5$$a10.1158/1538-7445.AM2023-234$$gVol. 83, no. 7_Supplement, p. 234 - 234$$x1538-7445$$y2023
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