Integrated systems-genetic analyses reveal a network target for delaying glioma progression

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Title: Integrated systems-genetic analyses reveal a network target for delaying glioma progression
Authors: Laaniste, L
Srivastava, P
Stylianou, T
Syed, N
Cases-Cunillera, S
Shkura, K
Zeng, Q
Rackham, O
Langley, S
Delahaye-Duriez, A
O'Neill, K
Williams, M
Becker, A
Roncaroli, F
Petretto, E
Johnson, M
Item Type: Journal Article
Abstract: Objective: To identify a convergent, multitarget proliferation characteristic for astrocytoma transformation that could be targeted for therapy discovery. Methods: Using an integrated functional genomics approach, we prioritised networks associated with astrocytoma progression using the following criteria: differential co-expression between grade II and grade III IDH1-mutated and 1p/19q euploid astrocytomas, preferential enrichment for genetic risk to cancer, association with patient survival and sample-level genomic features. Drugs targeting the identified multitarget network characteristic for astrocytoma transformation were computationally predicted using drug transcriptional perturbation data and validated using primary human astrocytoma cells. Results: A single network, M2, consisting of 177 genes, was associated with glioma progression on the basis of the above criteria. Functionally, M2 encoded physically interacting proteins regulating cell cycle processes and analysis of genome-wide gene-regulatory interactions using mutual information and DNA-protein interactions revealed the known regulators of cell cycle processes FoxM1, B-Myb and E2F2 as key regulators of M2. These results suggest functional disruption of M2 via gene mutation or altered expression as a convergent pathway regulating astrocytoma transformation. By considering M2 as a multitarget drug target regulating astrocytoma transformation, we identified several drugs predicted to restore M2 expression in anaplastic astrocytoma toward its low-grade profile and of these, we validated the known antiproliferative drug resveratrol as down-regulating multiple nodes of M2 including at nanomolar concentrations achievable in human cerebrospinal fluid by oral dosing. Interpretation: Our results identify M2 as a multitarget network characteristic for astrocytoma progression and encourage M2- based drug screening to identify new compounds for preventing glioma transformation.
Issue Date: 17-Aug-2019
Date of Acceptance: 28-Jun-2019
URI: http://hdl.handle.net/10044/1/71755
ISSN: 2328-9503
Publisher: Wiley Open Access
Journal / Book Title: Annals of Clinical and Translational Neurology
Copyright Statement: This paper is embargoed until publication. Once published it will be available fully open access.
Sponsor/Funder: UCB Biopharma SPRL
Funder's Grant Number: PO - 4400320473
Publication Status: Accepted
Embargo Date: publication subject to indefinite embargo
Appears in Collections:Clinical Sciences
National Heart and Lung Institute
Molecular Sciences
Department of Medicine



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