Christopher Dardis1, David Donner2, Nader Sanai3, Joanne Xiu4, Sandeep Mittal5, Sharon K Michelhaugh5, Manjari Pandey6, Santosh Kesari7, Amy B Heimberger8, Zoran Gatalica9, Michael W Korn4, Ashley L Sumrall10, Surasak Phuphanich11. 1. Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA. christopherdardis@gmail.com. 2. School of Medicine, Creighton University, Phoenix, AZ, USA. 3. Barrow Brain Tumor Research Center, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA. 4. Precision Oncology Alliance, Caris Life Sciences, Phoenix, AZ, USA. 5. Fralin Biomedical Research Institute, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA. 6. Department of Medical Oncology, West Cancer Center, University of Tennessee Health Science Center, Germantown, TN, USA. 7. Pacific Neuroscience Institute and Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, CA, USA. 8. Simpson Querry Biomedical Research Center, Department of Neurosurgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. 9. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 10. Department of Medical Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA. 11. Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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.
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.
Authors: S-H Kim; E-J Kim; M Hitomi; S-Y Oh; X Jin; H-M Jeon; S Beck; X Jin; J-K Kim; C G Park; S-Y Chang; J Yin; T Kim; Y-J Jeon; J Song; Y C Lim; J D Lathia; I Nakano; H Kim Journal: Cell Death Differ Date: 2015-02-27 Impact factor: 15.828
Authors: Olga Piskareva; Harry Harvey; John Nolan; Ross Conlon; Leah Alcock; Patrick Buckley; Paul Dowling; Michael Henry; Finbarr O'Sullivan; Isabella Bray; Raymond L Stallings Journal: Cancer Lett Date: 2015-05-07 Impact factor: 8.679
Authors: J Kononen; L Bubendorf; A Kallioniemi; M Bärlund; P Schraml; S Leighton; J Torhorst; M J Mihatsch; G Sauter; O P Kallioniemi Journal: Nat Med Date: 1998-07 Impact factor: 53.440