Path-05. primary and secondary gliosarcoma: radiological and prognostic differences using comprehensive multi-omics analysis

Abstract Purpose Gliosarcoma (GS), a rare variant of glioblastoma (GB), is further classified into primary (de novo) gliosarcoma (PGS), and secondary gliosarcoma (SGS), which is defined as recurrence after a diagnosis of diffuse glioma. Poorer survival of SGS than PGS has been reported, however, the detailed mechanism remains unknown. METHODS: A retrospective retrieval of pathological confirmed GS was performed. All the clinical, radiological, and pathological comparisons were based on the diagnosis of GS. A multi-omics, including whole exome sequencing, transcriptome, proteome and phosphoproteome, approach was used to acquire the molecular profiles of these specimens. RESULTS: From 2003 to 2020, a total of 28 GSs were identified, including 19 PGSs and 9 SGSs. The age tended to be younger in SGS group than PGS group (52.1 ± 10.9 vs. 60.8 ± 11.5, p=0.069). SGSs tended to present with dural attachment (p=0.071) and were significantly associated with major vessel encasement (p=0.002) than PGSs. The Ki-67 index tended to be higher in SGSs than PGSs (p=0.081). The GS survival was significantly shorter in SGS group than PGS group (median: 7.9 vs. 32.4 months, p< 0.001). The multi-omics analysis demonstrated SGSs had significantly higher expression of negative regulation of megakaryocyte differentiation, telomere capping, and DNA replication nucleosome assembly pathways than PGSs. Next, using proteome / phosphoproteome nonnegative matrix factorization analysis, PGS was categorized into two clusters (PGS_C1 versus PGS_C2) with distinct multi-omics features. Of which, PGS_C1 (n=4) tended to have shorter survival than PGS_C2 (n=15, p=0.054). Notably, the survival of patients in PGS_C1, who had similar multi-omics signature to SGS, were as poor as those of SGSs. CONCLUSIONS: In summary, this study provides, for the first time, in depth evidence for understanding GS and presents multi-omics biomarkers with prognostic significance. Further therapeutic translation should based on current findings to benefit GS patients.