Abstract IA19: Emerging genetic mechanisms in undifferentiated round cell sarcomas

Abstract

Abstract Undifferentiated round cell sarcomas (URCS) occurring in pediatric and young adults are defined by a primitive morphology reminiscent of Ewing sarcoma, but lack the canonical EWSR1-ETS gene fusion. More than >90% of EWSR1-negative URCS are instead characterized by either a CIC-DUX4 fusion or a genetic abnormality involving BCOR. The latter group includes intra-chromosomal paracentric inversions (BCOR-CCNB3), inter-chromosomal fusions (BCOR-MAML3), or BCOR internal tandem duplications (ITD). Irrespective of their variable mechanism for dysregulation, the tumors share a similar phenotype and a BCOR upregulation at transcriptional and protein levels. In contrast, CIC-DUX4 URCS are characterized by a distinct transcriptional upregulation of PEA3 transcription factors (ETV1/4/5). For practical and treatment purposes, URCS have been regarded as “Ewing sarcoma-like” and have been managed similarly to the Ewing sarcoma family of tumors, despite their poor chemotherapy responses and aggressive clinical behavior. Alternatively these tumors are grouped by default in an “undifferentiated sarcoma category,” with their clinical management being often biased. Despite the wide spectrum of genetic abnormalities, the unifying concept is that the various gene partners or ITDs disrupt the C-terminal repressor domains of both CIC and BCOR, resulting in an oncogenic transcriptional activation of target genes. In URCS with BCOR ITD, the ITD sequences located at the C-terminal may affect the PUFD domain conformation of the BCOR protein, which might interfere with PCGF1 binding and thus could affect the PRC1-related epigenetic modifications. Citation Format: Cristina Antonescu. Emerging genetic mechanisms in undifferentiated round cell sarcomas [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA19.