Abstract 2152: Targetable oncogenic fusions and other alterations in bone and soft-tissue tumors assessed by RNA and DNA-based next-generation sequencing in real-world experience
Authors: Dong Rongfang , Li Lan , Gong Lihua , Tian Mengmeng , Zhang Tingting , Zhang Wen , Ding Yi 
Published: April 2023

Background: Bone and soft-tissue tumors, especially soft-tissue sarcoma may have an underlying genetic mechanism, where fusion oncoproteins serve as drivers of the disease. This genetic simplicity provides an exceptional opportunity to develop effective and specific therapies. Here, we used RNA and DNA- based next-generation sequencing (NGS) to identify potentially druggable oncogene fusions in our patients that can be used for clinical trial involvement.

Methods: Pediatric and adult patients with bone and soft tissue tumors treated in our hospital undergoing biopsy or surgery were enrolled. Fusion transcript detection and mutation analysis in formalin-fixed, paraffin-embedded (FFPE) tumor samples were studied by both DNA-based next-generation sequencing (NGS) assay (520-gene panel) (Burning Rock OncoScreen Plus, Burning Rock Biotech, China) and targeted RNA platform (115 fusion-related-gene panel) (OncoRNA, Burning Rock Biotech, China) to identify additional molecular alterations and to potentially aid in patient management.

Results: Among 99 enrolled patients (108 tissue samples), 62.6% of patients were diagnosed as soft-tissue sarcoma. DNA-based NGS detected 108 tissue samples from 99 patients. RNA-based NGS successfully detected 99 samples from 91 patients, excluding 9 RNA-degraded samples. Oncogenic fusions were identified in 50.5% (46/91) of patients by RNA-based NGS. At least 2 kinds of fusion transcripts were detected in 18 patients. The fusion transcripts in only 5 cases detected by DNA-based NGS matched with the results by RNA-based NGS. The most frequent fusion partners were EWSR1 (n=12), DDIT3 (n=7), and PLAG1 (n=6). Six patients (6.6%) with druggable or potential druggable fusion for genetically matched therapies, including a case of NTRK-rearranged neoplasm patient with ETV6::NTRK3 fusion (TRK inhibitors), two cases of spindle cell tumors with RAF1 fusions (MEK inhibitors), a case of Ewing sarcoma with EWSR1::FLI1 fusion (ETS inhibitors), a case of FGFR1 fusion (FGFR inhibitors) and a case of ALK fusion (ALK inhibitors). A total of 50 patients were identified with actionable alterations by DNA-based NGS. Actionable alterations were most often located in MDM2 amplification (n=13), CDK4 amplification (n=12), and CDKN2A deletion (n=8).

Conclusion: The combination of RNA and DNA-based NGS techniques brings relevant information about tumor molecular alterations into the precision management of patients with bone and soft-tissue tumors. Those with tumors harboring targetable gene fusions and other alterations may benefit from target therapy, especially in the case of limited or exhausted standard therapy.

Citation Format: Rongfang Dong, Lan Li, Lihua Gong, Mengmeng Tian, Tingting Zhang, Wen Zhang, Yi Ding. Targetable oncogenic fusions and other alterations in bone and soft-tissue tumors assessed by RNA and DNA-based next-generation sequencing in real-world experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2152.