YAP/TAZ cooperate with AP-1 to drive the mesenchymal cell state in neuroblastoma (AWARDED BEST FIRE-SESSION ABSTRACT)

Background: Despite advancements in therapy, over 50% of highrisk neuroblastoma (NB) cases relapse after treatment, facing dismal prognosis.To date, there have been no extensive studies on the molecular and the immune landscape of relapsed NB and their potential in guiding future therapy concepts.Precision medicine programs and molecular profiling platforms provide opportunities for the detection of new biomarkers that may lead to new clinical trials in NB relapse.Methods/Patients: Patients included in this study were registered under the INFORM and MAPPYACTS precision oncology programs.Lowcoverage whole-genome sequencing (lcWGS), whole-exome sequencing (WXS), RNAseq and DNA methylation data were analyzed to identify mutational patterns, epigenetic subgroups, expressional features and subtypes with different immunogenicity of NB relapse tumors.Results: WXS and lcWGS data of 293 NB relapse tumors showed enrichment of frequent alterations in potentially targetable cancer driver pathways (RTK/RAS (45%), ALK (24%), cell cycle (18.7%)).DNA methylation analysis showed four molecular subgroups with distinct genetic characteristics, such as enrichment of cell-cycle gene alterations, and immune-related features.2 of 4 clusters showed high relative immunogenicity across different immune scoring systems with high expression of signatures related to MHC expression and effector cells, but also for anti-inflammatory cell types (Treg, MDSC) and the JAK-STAT pathway, a potential driver of the diverse TME.High immune scores also correlated with PD-L1 expression.Detailed profiling of the TME in relapse samples could improve stratification of patients for immune-based therapies.Integration of all data resulted in allocation into potential basket trial arms that could guide future NB relapse trial designs. Conclusion:Our study describes the first extensive multi-omics NB relapse cohort.High frequency of driver mutations and the detection of subgroups with high immune-scores potentially driven by JAK-STAT indicate opportunities for targeted therapy designs.Results of this study can be used as guidance for new NB relapse trials.