ElHarouni, Dina

Jager, Natalie

Milde, Till

Oppermann, Sina

Peterziel, Heike

Schlesner, Matthias

Schramm, Kathrin

Witt, Olaf

Öhme, Ina

OPUS Augsburg

                  Multiomics analysis of pediatric solid tumors within the INFORM precision oncologystudy: From functional drug profiling to biomarker identification.Dina ElHarouni, Heike Peterziel, Kathrin Schramm, Till Milde, Sina Oppermann, Ina Oehme, OlafWitt, Matthias Schlesner, Natalie Jäger; Hopp Children’s Cancer Center Heidelberg (KiTZ), Faculty ofBiosciences, Heidelberg University, Clinical Cooperation Unit Pediatric Oncology, German Cancer Re-search Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg,Germany; Hopp Children’s Cancer Center Heidelberg (KiTZ), Clinical Cooperation Unit Pediatric On-cology, German Cancer Research Center (DKFZ); German Consortium for Translational Cancer Re-search (DKTK), Heidelberg, Germany; Hopp Children’s Cancer Center Heidelberg (KiTZ), Division ofPediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium(DKTK), Heidelberg, Germany; KiTZ Clinical Trial Unit, Hopp Children’s Cancer Center Heidelberg(KiTZ), German Cancer Research Center (DKFZ) and Heidelberg University Hospital, Heidelberg, Ger-many; Hopp Children’s Cancer Center Heidelberg (KiTZ), Clinical Cooperation Unit Pediatric Oncology,German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research(DKTK), Heidelberg, Germany; Hopp Children’s Cancer Center Heidelberg (KiTZ), Clinical CooperationUnit Pediatric Oncology, German Cancer Research Center (DKFZ), Department of Hematology and On-cology, Heidelberg University Hospital, Heidelberg, Germany; Biomedical Informatics, Data Miningand Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg,Augsburg, Germany., Augsburg, Germany; Hopp Children’s Cancer Center Heidelberg (KiTZ), Divisionof Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, GermanyBackground: Within the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood)registry over 1200 childhood malignancies were molecularly profiled using next generation sequencingto identify therapeutic targets. Nevertheless, high evidence targets were only detected in 5% of casesand only 50% of the patients were identified with druggable pathways, while the remaining caseslacked druggable alterations. Thus, an ex-vivo functional drug response profiling platform for pediatricsolid tumors has been established within the INFORM program to identify novel biomarkers and unrav-el molecular mechanisms associated with drug response profiles for clinical translation. Methods: Solidtumors from 97 paediatric patients were screened against a library of 76 drugs. A quality control clas-sification decision tree was designed to select the samples for further analysis. Whole exome sequenc-ing, low-coverage whole genome sequencing, and RNA-seq were used to analyze the molecular profilesof the samples. Molecular features were filtered to retain oncogenic and druggable events. Five datafeature views (mutations, mRNA, gene fusions, CNVs, and drug responses) were used to train a Multi-Omics Factor Analysis (MOFA) model to identify prominent latent factors. Results: 81 samples passedthe quality control inclusion criteria of which 76 samples had available omics data profiles. Quantita-tive drug profiling measurements were reported using the selective asymmetric drug sensitivity score.-The multi-omics analysis captured five entity-specific omics signatures of Ewing sarcoma, Wilmstumor, BCOR sarcoma, neuroblastoma and ependymoma. Moreover, the analysis revealed sensitivity tonavitoclax in neuroblastoma samples with PHOX2B-GATA3 overexpression, and an association be-tween MEK inhibitor sensitivity and an expression signature in Wilms tumors. Conclusions: The combi-nation of functional drug and multi-omics profiling enabled the identification of novel biomarkers fordrug sensitivities in pediatric solid tumors. As we continue to expand the number of patient samplesevaluated with our drug sensitivity platform, this dataset will provide insights for novel drug targets,and could unravel key molecular events and mechanisms acting towards personalized therapies. Re-search Sponsor: German Cancer Consortium (DKTK), the German Cancer Aid (DKH), the GermanChildhood Cancer Foundation (DKS), the German Cancer Research Center (DKFZ) and “Ein Herz f€urKinder”, Other Foundation.                                                                                                                                                                                                                                                                                                      

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Multiomics analysis of pediatric solid tumors within the INFORM precision oncology study: from functional drug profiling to biomarker identification [Abstract]

Multiomics analysis of pediatric solid tumors within the INFORM precision oncology study: from functional drug profiling to biomarker identification [Abstract]

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