Genomic landscape of gliosarcoma: distinguishing features and targetable alterations

Abstract

Gliosarcoma is an aggressive brain tumor with histologic features of glioblastoma (GBM) and soft tissue sarcoma. Despite its poor prognosis, its rarity has precluded analysis of its underlying biology. We used a multi-center database to characterize the genomic landscape of gliosarcoma. Sequencing data was obtained from 35 gliosarcoma patients from Genomics Evidence Neoplasia Information Exchange (GENIE) 5.0, a database curated by the American Association of Cancer Research (AACR). We analyzed genomic alterations in gliosarcomas and compared them to GBM (n = 1,449) and soft tissue sarcoma (n = 1,042). 30 samples were included (37% female, median age 59 [IQR: 49-64]). Nineteen common genes were identified in gliosarcoma, defined as those altered in > 5% of samples, including TERT Promoter (92%), PTEN (66%), and TP53 (60%). Of the 19 common genes in gliosarcoma, 6 were also common in both GBM and soft tissue sarcoma, 4 in GBM alone, 0 in soft tissue sarcoma alone, and 9 were more distinct to gliosarcoma. Of these, BRAF harbored an OncoKB level 1 designation, indicating its status as a predictive biomarker of response to an FDA-approved drug in certain cancers. EGFR, CDKN2A, NF1, and PTEN harbored level 4 designations in solid tumors, indicating biological evidence of these biomarkers predicting a drug-response. Gliosarcoma contains molecular features that overlap GBM and soft tissue sarcoma, as well as its own distinct genomic signatures. This may play a role in disease classification and inclusion criteria for clinical trials. Gliosarcoma mutations with potential therapeutic indications include BRAF, EGFR, CDKN2A, NF1, and PTEN.

Figure 1

Recurrent genetic alterations in gliosarcoma. Summary of major alterations in 19 most frequently altered genes and pathways in gliosarcoma. Labels on left represent major biological pathways altered by each group of genes, and genes are ordered within each group in order of decreasing incidence. By functional categorization and descending order of mutation frequency: Cell Migration and Proliferation: NF1 (41%), EGFR (12%), Cell Cycle Regulation: CDKN2B (28%), RB1 (26%), ANKRD11 (11%), Cell Proliferation and Survival: PTEN (66%), CDKN2A (31%), SOX2 (11%), BRAF (10%), Apoptosis: TP53 (60%), Genetic Stability: TERT Promoter (92%), STAG2 (22%), ARID2 (11%), Mismatch repair: MSH6 (11%), and Miscellaneous: CBL (11%), CREBBP (11%), SUZ12 (11%), PTPN11 (10%). Order of samples determined by hierarchical clustering. Bar plots above and to the right represent number of alterations per sample and per gene, respectively.

Figure 2

Genetic alteration comparison. Venn diagram of representative commonly altered genes in gliosarcoma, glioblastoma (GBM), and soft tissue sarcoma.

Figure 3

Comparative incidence of common alterations between GBM and gliosarcoma. Incidence of alterations which significantly differed between gliosarcoma and GBM (Fisher’s Exact Test p < 0.05), although no differences retained significance after multiple hypothesis correction.