Mapping genomic heterogeneity in paediatric and adolescent-young adult sarcomas: insights from the Italian SAR-GEN2016 and SAR-GENITA prospective multicenter trials

Abstract Sarcomas in paediatric and adolescent-young adult populations represent rare and biologically heterogeneous tumours with complex genetic underpinnings. Genomic profiling reveals subtype-specific alterations and therapeutic targets. Such tumours still represent an unmet clinical need due to limited treatment options and poorer outcomes, especially in advanced stages. Here, we present the SAR-GEN2016 and SAR-GENITA clinical trials, conducted across 12 Italian centres, which enrolled 201 patients including 158 bone and soft tissue sarcoma samples collected at diagnosis or relapse. Whole-exome sequencing was successfully performed on 120 tumour samples. The most representative histotypes were Osteosarcoma (OS, n=53), Ewing’s sarcoma (EW, n=39), Rhabdomyosarcoma (n=13), and Synovial sarcoma (n=5), and the genomic analyses were mainly focused on these subtypes. Overall, our cohort showed genomic differences between subtypes, highlighting how genomic complex sarcomas and fusion-driven sarcomas are distinct entities. The genomic complex histotypes, such as OS, were characterised by a lower tumour mutational burden (TMB), and higher copy number variation burden with enrichment of the CN2 signature. Recurrent and metastatic EWs have a higher TMB compared to treatment-naïve primary tumours, along with increased intratumoural heterogeneity. Oncogenic pathway analyses revealed dysregulation of the RTK-RAS and NOTCH pathways across subtypes, particularly in metastatic and recurrent tumours. In 71 out of 120 analysed samples (59%), at least one potentially actionable genomic alteration was identified, and 16% of those patients with relapsed disease received a matched targeted therapy based on the molecular profiling results. All findings were classified as ESCAT Tier IIorIII. Our findings support the value of integrating genomic and clinical data to accelerate translational research in rare tumours.