(P 010) SPECTRUM OF EWING-LIKE FUSIONS AND SECONDARY GENOMIC ALTERATIONS FROM A LARGE NEXT GENERATION SEQUENCING (NGS) COMPREHENSIVE GENOMIC PROFILING (CGP) DATABASE

Objective: Cancers previously described as “Ewing-like” sarcomas are now understood to include a diverse group of fusion-positive sarcomas including EWSR1 round cell sarcoma with non-ETS fusions, CIC-rearranged sarcomas, and sarcomas with BCOR alterations. These tumors are histologically, genomically, and clinically distinct, although like Ewing sarcoma affect adolescents and young adults. The prevalence of these diagnoses and the full spectrum of their genomic profiles have not been fully described.

Methods: A retrospective cohort of 19702 clinically advanced extra-cranial sarcomas evaluated by routine hybrid-capture based targeted comprehensive genomic profiling (CGP) was evaluated. Tumor mutational burden (TMB) was determined on at least 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined using at least 1500 loci. The cohort was refined to EWSR1 or FUS-rearranged round cell sarcoma with non-ETS partners, CIC sarcomas, and BCOR sarcomas. Specimens with EWSR1 or FUS translocated with partners characteristic for another specific named entity (e.g., WT1 or ATF) were excluded.

Results: Based upon knowledge of both fusion partners, molecular reclassification yielded 344 (1.7%) cases of Ewing-like sarcomas. Among Ewing-like sarcomas, 32.8% were EWSR1-non-ETS partner fusions (n=113; most common partners were PATZ1 [11], NFATC2 [11] & TFCP2 [10]), 33.1% were BCOR sarcomas (n=114; most common partners were ZC3H7B [54], CCNB3 [20] & CREBBP [4]) and 34.0% were CIC-rearranged sarcomas (n=117; most common partners were DUX4 [65], NUTM1 [4] & MEGF8 [4]). Of the 344 cases, 129 (37.5%) had pre-sequencing clinical diagnoses other than soft tissue sarcoma. Only 1 specimen had TMB >10 (15mut/Mbp) and it was also MSI-high. The most common secondary genomic alterations among patients with Ewing-like sarcomas were pathogenic alterations in CDKN2A (19.5%), MDM2 (14.8%), CDKN2B (14.5%), TP53 (13.9%), CDK4 (13.4%), FRS2 (12.8%), and RB1 (6.1%).

Conclusion: The prevalence of “Ewing-like” sarcoma is low and the spectrum of fusion partners diverse, yet many of these diagnoses may be misclassified without a comprehensive molecular diagnosis. Amplifications in MDM2 and CDK4 are potentially targetable genomic events in this population.