通过泛癌CGP与定制化肉瘤融合检测相结合，识别软组织肉瘤患者的分子改变

Introduction: The genomic characterization of soft tissue sarcomas is increasingly applied in patient care to help understand the pathogenesis of these diseases. However, most pan-cancer comprehensive genomic profiling (CGP) tests cover few gene fusions of clinical relevance in sarcomas. Hence, the contribution of all classes of genomic alterations to the pathogenesis of sarcomas often has a methodological bias. Objective: This study investigates all actionable genomic variants present in soft tissue sarcoma patients using a sarcoma-targeted CGP approach that also interrogates most sarcoma-relevant gene fusions. Methodology: We screened 20660 test orders for cancer patients with available diagnosis tested by either of two complementary tests: a pan-cancer CGP panel and a sarcoma fusion panel, both routinely performed in our clinical laboratory. The first detects SNV/Indels in 517 genes, CNA in 59 genes, MSI and TMB, and common solid tumor RNA fusions in 55 genes. The second analyzes additional known and novel RNA fusions in 97 genes with high diagnostic, prognostic, and therapeutic value in sarcomas, utilizing fusion enrichment-based RNA-seq. Out of 12885 CGP tested patients, 346 had sarcoma, while 1406 sarcoma patients were tested with the sarcoma fusion panel. Of those, 62 patients were characterized using both tests. Results: From the 346 sarcoma patients tested with the pan-cancer CGP test, 268 patients had pathogenic DNA alterations, and 22 patients had RNA fusions. Conversely, among 1406 sarcoma patients tested with the sarcoma fusion panel, fusions were detected in 399 patients, with 207 distinct fusions identified. The top 5 genes rearranged were EWSR1, HMGA2, FUS, FLI1, and SS18. We next analyzed the data from the 62 sarcoma patients tested with both assays and found that pathogenic alterations (DNA/RNA) were detected in 56 cases. DNA alterations were found in 54 of them. SNV/indels were present in 53 patients with 86 genes harboring pathogenic mutations, most frequently in TP53, TERT, LRP1B, NF1, TET, and CDKN2A. CNAs were identified in 15 patients, of whom one had only CNAs (KRAS, MDM2, PDGFRA, and KIT). The most frequent CNAs were in MDM2 (n=5), followed by CCND1, CDK4, EGFR, KRAS, and MYC (n=3). Gene fusions were detected in 10 patients. Three (3) patients had fusions detected by both panels, 2 had fusions detected by the CGP panel but not covered by the sarcoma panel, and 5 patients had a fusion only detected by the Sarcoma fusion panel. Conclusions: Comprehensive genomic profiling of sarcomas with pan-cancer targeted panels unveiled the pathogenic molecular landscape in sarcoma patients from the community. Additional testing with a sarcoma-targeted fusion panel significantly enhanced the identification of pathogenic fusions, enabling a more comprehensive evaluation of the contribution of gene fusions to both pathogenesis and patient care.