Impaired neutrophil-mediated cell death drives Ewing's Sarcoma in a two years old child with Down Syndrome

Ewing's Sarcoma (EWS) has been reported in seven children with Down Syndrome (DS). To date, a detailed assessment of this solid tumor in DS patients is still missing. Here, we characterized a chemo-resistant mediastinal EWS in a 2-year-old DS child, the youngest ever reported case, by exploiting sequencing approaches. The tumor showed a neuroectodermal development driven by the EWSR1-FLI1 fusion. The inherited myeloperoxidase deficiency of the patient caused failure of neutrophil-mediated cell death and promoted genomic instability. In this context, the tumor underwent nearly genome-wide haploidization resulting in a massive overexpression of pro-inflammatory cytokines. Recruitment of defective neutrophils fostered the fast evolution of this EWS. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04621201 ### Funding Statement The research leading to these results has received funding from AIRC under MFAG 2017 ID 20566 (to M.C.), Ricerca Finalizzata 2019 ID GR-2019-12368827 (to M.C.), FPRC 5xmille 2018 Ministero Salute, project "ADVANCE/A-Bi-C": Italian Ministry of Health, Ricerca Corrente 2021 (to M.C.), Compagnia di San Paolo (to M.C. and F.F.), and Fondazione Umberto Veronesi (to F.F.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The patient was enrolled in the clinical trial entitled Genomic Profile Analysis in Children, Adolescents and Young Adult with Sarcomas - SAR_GEN-ITA (ClinicalTrials.gov ID:[NCT04621201][1]). The trial was approved on 30th November 2018 by the independent ethics committees of A.O.U Cittá della Salute e della Scienza di Torino - A.O. Ordine Mauriziano - A.S.L. Cittá di Torino (Turin, Italy) and it was conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice. Parents were provided with written informed consent for the analysis and data publication. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04621201&atom=%2Fmedrxiv%2Fearly%2F2023%2F05%2F31%2F2023.05.30.23289664.atom