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Abstract：
BACKGROUND: Gliosarcoma (GS) refers to the presence of mesenchymal differentiation (as seen using light microscopy) in the setting of glioblastoma (GB, an astrocytoma, WHO Grade 4). Although the same approach to treatment is typically adopted for GS and GB, there remains some debate as to whether GS should be considered a discrete pathological entity. Differences between these tumors have not been clearly established at the molecular level.
METHODS: Patients with GS (n=48) or GB (n=1229) underwent molecular profiling (MP) with a pan-cancer panel of tests as part of their clinical care. The methods employed included next-generation sequencing (NGS) of DNA and RNA, copy number variation (CNV) of DNA and immunohistochemistry (IHC). The MP comprised 1153 tests in total, although results for each test were not available for every tumor profiled. We analyzed this data retrospectively in order to determine if our results were in keeping with what is known about the pathogenesis of GS by contrast with GB. We also sought novel associations between the MP and GS vs. GB which might improve our understanding of pathogenesis of GS.
RESULTS: Potentially meaningful associations (p<0.1, Fisher\'s exact test (FET)) were found for 14 of these tests in GS vs. GB. A novel finding was higher levels of proteins mediating immuno-evasion (PD-1, PD-L1) in GS. All of the differences we observed have been associated with epithelial-to-mesenchymal transition (EMT) in other tumor types. Many of the changes we saw in GS are novel in the setting of glial tumors, including copy number amplification in LYL1 and mutations in PTPN11.
CONCLUSIONS: GS shows certain characteristics of EMT, by contrast with GB. Treatments targeting immuno-evasion may be of greater therapeutic value in GS relative to GB.
METHODS: Patients with GS (n=48) or GB (n=1229) underwent molecular profiling (MP) with a pan-cancer panel of tests as part of their clinical care. The methods employed included next-generation sequencing (NGS) of DNA and RNA, copy number variation (CNV) of DNA and immunohistochemistry (IHC). The MP comprised 1153 tests in total, although results for each test were not available for every tumor profiled. We analyzed this data retrospectively in order to determine if our results were in keeping with what is known about the pathogenesis of GS by contrast with GB. We also sought novel associations between the MP and GS vs. GB which might improve our understanding of pathogenesis of GS.
RESULTS: Potentially meaningful associations (p<0.1, Fisher\'s exact test (FET)) were found for 14 of these tests in GS vs. GB. A novel finding was higher levels of proteins mediating immuno-evasion (PD-1, PD-L1) in GS. All of the differences we observed have been associated with epithelial-to-mesenchymal transition (EMT) in other tumor types. Many of the changes we saw in GS are novel in the setting of glial tumors, including copy number amplification in LYL1 and mutations in PTPN11.
CONCLUSIONS: GS shows certain characteristics of EMT, by contrast with GB. Treatments targeting immuno-evasion may be of greater therapeutic value in GS relative to GB.
摘要：
背景：胶质肉瘤（GS）是指在胶质母细胞瘤的背景下存在间质分化（如使用光学显微镜所见）（GB，星形细胞瘤,世卫组织4级）。尽管GS和GB通常采用相同的治疗方法，关于GS是否应被视为离散的病理实体，仍存在一些争论。这些肿瘤之间的差异尚未在分子水平上明确确定。
方法：患有GS（n=48）或GB（n=1229）的患者接受了分子谱分析（MP）和一组泛癌症测试，作为其临床护理的一部分。采用的方法包括DNA和RNA的下一代测序（NGS），DNA拷贝数变异(CNV)和免疫组织化学(IHC)。MP总共包括1153项测试，尽管并非每个肿瘤都有每项检查的结果。我们回顾性分析了这些数据，以确定我们的结果是否与已知的GS与GB的发病机理相一致。我们还寻求MP和GS与这可能会提高我们对GS发病机制的认识。
结果：在GS与GS中发现了其中14项测试的潜在有意义的关联（p<0.1，Fisher精确检验（FET））。GB一个新发现是GS中介导免疫逃避的蛋白质水平较高（PD-1，PD-L1）。我们观察到的所有差异都与其他肿瘤类型的上皮间质转化（EMT）有关。我们在GS中看到的许多变化在神经胶质肿瘤的背景下都是新颖的，包括LYL1中的拷贝数扩增和PTPN11中的突变。
结论：GS显示EMT的某些特征，与GB相比。相对于GB,靶向免疫逃避的治疗在GS中可能具有更大的治疗价值。
方法：患有GS（n=48）或GB（n=1229）的患者接受了分子谱分析（MP）和一组泛癌症测试，作为其临床护理的一部分。采用的方法包括DNA和RNA的下一代测序（NGS），DNA拷贝数变异(CNV)和免疫组织化学(IHC)。MP总共包括1153项测试，尽管并非每个肿瘤都有每项检查的结果。我们回顾性分析了这些数据，以确定我们的结果是否与已知的GS与GB的发病机理相一致。我们还寻求MP和GS与这可能会提高我们对GS发病机制的认识。
结果：在GS与GS中发现了其中14项测试的潜在有意义的关联（p<0.1，Fisher精确检验（FET））。GB一个新发现是GS中介导免疫逃避的蛋白质水平较高（PD-1，PD-L1）。我们观察到的所有差异都与其他肿瘤类型的上皮间质转化（EMT）有关。我们在GS中看到的许多变化在神经胶质肿瘤的背景下都是新颖的，包括LYL1中的拷贝数扩增和PTPN11中的突变。
结论：GS显示EMT的某些特征，与GB相比。相对于GB,靶向免疫逃避的治疗在GS中可能具有更大的治疗价值。
