(P 452) SECONDARY GENOMIC LANDSCAPE OF CIC::DUX4 FUSION SARCOMAS

Objective: CIC::DUX4 fusion sarcomas are a distinct subset of high-grade undifferentiated round cell sarcomas characterized by a specific oncogenic translocation involving the CIC and DUX4 genes mostly in pediatric population. These sarcomas are rare and aggressive, and there remains a lack of consensus in how CIC::DUX4 sarcomas should be treated clinically. Beyond the disease-defining fusion event, there is limited knowledge about the secondary genomic landscape associated with these sarcomas. We have previously reported that other small round cell tumors often have associated secondary alterations. In this study, we assess this hypothesis through evaluation of the genomic landscape of CIC::DUX4 sarcomas.

Methods: Genomic profiling data of clinical sarcoma specimens were collected from those analyzed by Foundation Medicine from 2012 through 2018 as originally approved by the Western institutional review board (IRB 20152817). Tumors harboring CIC::DUX4 (or DUX4 family members) fusions were selected. Only known pathogenic genomic variants were included. Pathway analysis for genes and targetable gene variants were defined by MSK OncoKB.

Results: Out of a total of 7,494 sarcomas, 16 patients with CIC::DUX4 fusions were identified. An addition two patients exhibited a CIC::DUX4L fusion and two patients exhibited a CIC::DUX4L4 fusion. Patients were primarily female (n=14, 70.0%%) with a median age at sequencing of 31 years (inter-quartile range: 17.25-50.25 years). Tumor mutational burden was low (median: 0.8 mut/Mb; inter-quartile range: 0-3.0 mut/Mb) and no tumors were microsatellite instable. Of the 20 total patients included, 10 (50.0%) did not exhibit any additional genomic variants. Of the 10 patients that did have secondary variants a total of 14 unique pathogenic genomic variants were identified. Only CCT6B was identified in two tumors. We next analyzed whether these variants shared common molecular pathways. Common pathways noted included DNA damage response (4/20), growth signaling (3/20), and transcription regulation (n=4/20). Three patients exhibited potentially targetable gene variants according to OncoKB including ATM insertion (olaparib), CHEK2 copy number deletion (olaparib), and FGFR3 splice site variant (erdafitinib).

Conclusion: Secondary genomic variants are rare in CIC::DUX4 sarcomas and show few molecular similarities. Potentially targetable genomic variants were also rare. This data suggest that the driving oncogenic signal for this malignancy may solely be a function of the CIC::DUX4 fusion. Further prospective research is needed to confirm these findings.