**1. Introduction**

Sarcomas are heterogeneous cancers of bone or soft tissue. They occur in children as well as adolescents and young adults (AYAs). They are rare among adult malignancies but account for 12–15% of all pediatric tumors [1]. Despite the introduction and continued optimization of multimodal therapies, approximately one-third of sarcoma patients still die from the disease. Current therapies combine surgery, polychemotherapy, radiation, immunotherapy, and/or targeted therapeutics. Scientific advances have enabled more precise molecular characterization of sarcoma subtypes [2–4] and discovered new therapeutic targets and prognostic biomarkers [5]. Patients with primary metastatic disease or recurrence have a very poor prognosis in both age groups [6].

The pathogenesis of many sarcomas is poorly understood, but research over the past 20 years has identified recurrent, characteristic chromosomal translocations in approximately one-third of sarcomas (including most pediatric, adolescent, and young adult tumors). Chromosomal rearrangements resulting in oncogenic fusion genes are more common in childhood cancers than in adult tumors [7, 8].

The first sarcoma-specific chromosomal translocation was detected in 1982 in patients with alveolar rhabdomyosarcoma [9]. In subsequent years, chromosomal aberrations were identified in additional sarcomas [10]. These translocations are specific to the individual sarcomas and are considered tumor-initiating in those in which they occur [11, 12].

Fusion-positive sarcomas are characterized molecularly by a relatively quiescent genome with recurrent, balanced translocations leading to the formation of novel fusion oncogenes that are key to pathogenesis [13]. In these sarcomas, fusion proteinforming translocations are often the primary driver of disease pathogenesis and are accompanied by very few other mutations [14], although a limited number of recurrent, cooperating mutations have been identified (e.g., STAG2 in Ewing sarcomas and KRAS in synovial sarcomas) [15–19].

With the advent of advanced techniques in molecular genetics and pathology, new translocations in sarcomas are regularly reported, leading to reclassification and adjusted risk stratification. Many sarcomas are now diagnosed and classified or reclassified based on these underlying molecular alterations [2, 4, 20].

The marked tumor specificity, of the individual fusion genes, suggests that their oncogenic roles are specific to a particular cell type and/or developmental stage. Consistent with the consideration that factors related to developmental timing are associated with oncogenesis triggered by the fusion genes, many of these sarcomas occur primarily in children [8].

Unlike other cancers, these diseases contain chimeric and neomorphic proteins that are clonally present, and due to their tumor specificity and demonstrated role in tumorigenesis, these fusion proteins often represent unique and promising targets for therapeutic intervention and robust opportunities to cure these diseases [11, 12, 15, 21].
