Gliosarcoma: distinct molecular pathways and genomic alterations identified by DNA copy number/SNP microarray analysis

Abstract

Purpose Gliosarcoma is a histologic variant of glioblastoma (GBM), and like GBM carries a poor prognosis. Median survival is less than one (1) year with less than 5% of patients alive after 5 years. Although there is no cure, standard treatment includes surgery, radiation and chemotherapy. While very similar to GBM, gliosarcoma exhibits several distinct differences, morphologically and molecularly. Therefore, we report a comprehensive analysis of DNA copy number changes in gliosarcoma using a cytogenomic DNA copy number (CN) microarray (OncoScan ® ). Methods Cytogenomic DNA copy number microarray (OncoScan ® ) was performed on 18 cases of gliosarcoma. MetaCore™ enrichment was applied to the array results to detect associated molecular pathways. Results The most frequent alteration was copy number loss, comprising 57% of total copy number changes. The number of losses far exceeded the number of amplifications (***, < 0.001) and loss of heterozygosity events (***, < 0.001). Amplifications were infrequent (4.6%), particularly for EGFR . Chromosomes 9 and 10 had the highest number of losses; a large portion of which correlated to CDKN2A/B loss. Copy number gains were the second most common alteration (26.2%), with the majority occurring on chromosome 7. MetaCore™ enrichment detected notable pathways for copy number gains including: HOXA, Rho family of GTPases, and EGFR; copy number loss including: WNT, NF-kß, and CDKN2A; and copy number loss of heterozygosity including: WNT and p53. Conclusions The pathways and copy number alterations detected in this study may represent key drivers in gliosarcoma oncogenesis and may provide a starting point toward targeted oncologic analysis with therapeutic potential.

Clinical Characteristics of Gliosarcoma and Outcomes From Standardized Treatment Relative to Conventional Glioblastoma

“…Our PGS cohort was also demographically and clinically comparable with previous described cases of GS (37,39,49), patients were predominantly middle-aged men (M:F ratio 19:7, median age 59.7) with a tumor located in the temporal lobe (57.7%). Also, in concordance with GS being a variant of GBM, IDH-wildtype, and prior reported genetic alterations (50,51) all PGS tumors were IDH1-wildtype.…”

“…It was recently proposed that the GS diagnosis could be estimated by preoperatively imaging analysis (27), but this is conflicted by a study finding a slightly larger area of edema to be the only distinct feature of GS compared to conventional GBM tumors upon evaluation of the radiological VASARI feature set (51). Radiological analysis of our PGS patients revealed that 58% had a peripheral tumor abutting dura, consistent with previous reported imaging characteristics (28)(29)(30)(31).…”

Evaluating Surgical Resection Extent and Adjuvant Therapy in the Management of Gliosarcoma

“…Histologically, gliosarcomas can be distinguished by the biphasic presence of both glial and sarcomatous components (2)(3)(4). Molecular studies on gliosarcoma have suggested a monoclonal origin of these distinct cell populations prior to their divergent differentiation patterns based on the presence of shared somatic alterations, including that of tumor suppressors TP53 and PTEN (5)(6)(7).…”

Current Opinion on Molecular Characterization for GBM Classification in Guiding Clinical Diagnosis, Prognosis, and Therapy

“…Patients with the giant cell GBM have outcomes similar to classical GBM. In gliosarcoma, TP53 mutations are rare, and EGFR amplification is also uncommon, and contains CDKN2A deletion (Lowder et al, 2019). The clinical outcome of gliosarcoma differs from classical GBM, but there are still conflicting and uncertain results from various studies.…”