Eric M Thompson1, Stephen T Keir1, Talaignair Venkatraman1, Christopher Lascola1, Kristen W Yeom1, Andrew B Nixon1, Yingmiao Liu1, Daniel Picard1, Marc Remke1, Darell D Bigner1, Vijay Ramaswamy1, Michael D Taylor1. 1. Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Abstract
BACKGROUND: Of the 4 medulloblastoma subgroups, Group 3 is the most aggressive but the importance of angiogenesis is unknown. This study sought to determine the role of angiogenesis and identify clinically relevant biomarkers of tumor vascularity and survival in Group 3 medulloblastoma. METHODS: VEGFA mRNA expression and survival from several patient cohorts were analyzed. Group 3 xenografts were implanted intracranially in nude rats. Dynamic susceptibility weighted (DSC) MRI and susceptibility weighted imaging (SWI) were obtained. DSC MRI was used to calculate relative cerebral blood volume (rCBV) and flow (rCBF). Tumor vessel density and rat vascular endothelial growth factor alpha (VEGFA) expression were determined. RESULTS: Patient VEGFA mRNA levels were significantly elevated in Group 3 compared with the other subgroups (P < 0.001) and associated with survival. Xenografts D283, D341, and D425 were identified as Group 3 by RNA hierarchical clustering and MYC amplification. The D283 group had the lowest rCBV and rCBF, followed by D341 and D425 (P < 0.05). These values corresponded to histological vessel density (P < 0.05), rat VEGFA expression (P < 0.05), and survival (P = 0.002). Gene set enrichment analysis identified 5 putative genes with expression profiles corresponding with these findings: RNH1, SCG2, VEGFA, AGGF1, and PROK2. SWI identified 3 xenograft-independent categories of intratumoral vascular architecture with distinct survival (P = 0.004): organized, diffuse microvascular, and heterogeneous. CONCLUSIONS: Angiogenesis plays an important role in Group 3 medulloblastoma pathogenesis and survival. DSC MRI and SWI are clinically relevant biomarkers for tumor vascularity and overall survival and can be used to direct the use of antivascular therapies for patients with Group 3 medulloblastoma.
BACKGROUND: Of the 4 medulloblastoma subgroups, Group 3 is the most aggressive but the importance of angiogenesis is unknown. This study sought to determine the role of angiogenesis and identify clinically relevant biomarkers of tumor vascularity and survival in Group 3 medulloblastoma. METHODS: VEGFA mRNA expression and survival from several patient cohorts were analyzed. Group 3 xenografts were implanted intracranially in nude rats. Dynamic susceptibility weighted (DSC) MRI and susceptibility weighted imaging (SWI) were obtained. DSC MRI was used to calculate relative cerebral blood volume (rCBV) and flow (rCBF). Tumor vessel density and rat vascular endothelial growth factor alpha (VEGFA) expression were determined. RESULTS: Patient VEGFA mRNA levels were significantly elevated in Group 3 compared with the other subgroups (P < 0.001) and associated with survival. Xenografts D283, D341, and D425 were identified as Group 3 by RNA hierarchical clustering and MYC amplification. The D283 group had the lowest rCBV and rCBF, followed by D341 and D425 (P < 0.05). These values corresponded to histological vessel density (P < 0.05), rat VEGFA expression (P < 0.05), and survival (P = 0.002). Gene set enrichment analysis identified 5 putative genes with expression profiles corresponding with these findings: RNH1, SCG2, VEGFA, AGGF1, and PROK2. SWI identified 3 xenograft-independent categories of intratumoral vascular architecture with distinct survival (P = 0.004): organized, diffuse microvascular, and heterogeneous. CONCLUSIONS: Angiogenesis plays an important role in Group 3 medulloblastoma pathogenesis and survival. DSC MRI and SWI are clinically relevant biomarkers for tumor vascularity and overall survival and can be used to direct the use of antivascular therapies for patients with Group 3 medulloblastoma.
Authors: Marc Remke; Thomas Hielscher; Paul A Northcott; Hendrik Witt; Marina Ryzhova; Andrea Wittmann; Axel Benner; Andreas von Deimling; Wolfram Scheurlen; Arie Perry; Sidney Croul; Andreas E Kulozik; Peter Lichter; Michael D Taylor; Stefan M Pfister; Andrey Korshunov Journal: J Clin Oncol Date: 2011-05-31 Impact factor: 44.544
Authors: Yoon-Jae Cho; Aviad Tsherniak; Pablo Tamayo; Sandro Santagata; Azra Ligon; Heidi Greulich; Rameen Berhoukim; Vladimir Amani; Liliana Goumnerova; Charles G Eberhart; Ching C Lau; James M Olson; Richard J Gilbertson; Amar Gajjar; Olivier Delattre; Marcel Kool; Keith Ligon; Matthew Meyerson; Jill P Mesirov; Scott L Pomeroy Journal: J Clin Oncol Date: 2010-11-22 Impact factor: 44.544
Authors: Jason S Weinstein; Csanad G Varallyay; Edit Dosa; Seymur Gahramanov; Bronwyn Hamilton; William D Rooney; Leslie L Muldoon; Edward A Neuwelt Journal: J Cereb Blood Flow Metab Date: 2009-09-16 Impact factor: 6.200
Authors: Eric M Thompson; Daniel J Guillaume; Edit Dósa; Xin Li; Kellie J Nazemi; Seymur Gahramanov; Bronwyn E Hamilton; Edward A Neuwelt Journal: J Neurooncol Date: 2012-04-19 Impact factor: 4.130
Authors: Yingjen Jeffrey Wu; Leslie L Muldoon; Dana Thomas Dickey; Seth J Lewin; Csanad G Varallyay; Edward A Neuwelt Journal: Neoplasia Date: 2009-02 Impact factor: 5.715
Authors: V W Li; R D Folkerth; H Watanabe; C Yu; M Rupnick; P Barnes; R M Scott; P M Black; S E Sallan; J Folkman Journal: Lancet Date: 1994-07-09 Impact factor: 79.321
Authors: Eric M Thompson; Alexa Bramall; James E Herndon; Michael D Taylor; Vijay Ramaswamy Journal: J Neurooncol Date: 2018-05-23 Impact factor: 4.130
Authors: Eric M Thompson; Michael Brown; Elena Dobrikova; Vijay Ramaswamy; Michael D Taylor; Roger McLendon; Jennifer Sanks; Vidya Chandramohan; Darell Bigner; Matthias Gromeier Journal: J Neuropathol Exp Neurol Date: 2018-08-01 Impact factor: 3.685
Authors: Laura A Genovesi; Simon Puttick; Amanda Millar; Marija Kojic; Pengxiang Ji; Anne K Lagendijk; Caterina Brighi; Claudine S Bonder; Christelle Adolphe; Brandon J Wainwright Journal: Neuro Oncol Date: 2021-05-05 Impact factor: 12.300
Authors: Andrey Korshunov; Konstantin Okonechnikov; Damian Stichel; Daniel Schrimpf; Alberto Delaidelli; Svenja Tonn; Martin Mynarek; Philipp Sievers; Felix Sahm; David T W Jones; Andreas von Deimling; Stefan M Pfister; Marcel Kool Journal: Acta Neuropathol Date: 2022-06-30 Impact factor: 15.887