title: Causal Mechanistic Regulatory Network for Glioblastoma Deciphered Using Systems Genetics Network Analysis.
abstract: We developed the transcription factor (TF)-target gene database and the Systems Genetics Network Analysis (SYGNAL) pipeline to decipher transcriptional regulatory networks from multi-omic and clinical patient data, and we applied these tools to 422 patients with glioblastoma multiforme (GBM). The resulting gbmSYGNAL network predicted 112 somatically mutated genes or pathways that act through 74 TFs and 37 microRNAs (miRNAs) (67 not previously associated with GBM) to dysregulate 237 distinct co-regulated gene modules associated with patient survival or oncogenic processes. The regulatory predictions were associated to cancer phenotypes using CRISPR-Cas9 and small RNA perturbation studies and also demonstrated GBM specificity. Two pairwise combinations (ETV6-NFKB1 and romidepsin-miR-486-3p) predicted by the gbmSYGNAL network had synergistic anti-proliferative effects. Finally, the network revealed that mutations in NF1 and PIK3CA modulate IRF1-mediated regulation of MHC class I antigen processing and presentation genes to increase tumor lymphocyte infiltration and worsen prognosis. Importantly, SYGNAL is widely applicable for integrating genomic and transcriptomic measurements from other human cohorts.
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA. Electronic address: cplaisier@systemsbiology.org.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Plaisier
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
authors.forename: Sofie
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
authors.forename: Brady
authors.initials: B
authors.lastname: Bernard
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Reynolds
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
authors.forename: Zac
authors.initials: Z
authors.lastname: Simon
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Toledo
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Reiss
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Paddison
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA. Electronic address: nbaliga@systemsbiology.org.
authors.forename: Nitin S
authors.initials: NS
authors.lastname: Baliga
mesh_terms: D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005909:Glioblastoma; D006801:Humans; D035683:MicroRNAs; D009857:Oncogenes
chemical_list: D035683:MicroRNAs
keywords: gene regulation; glioblastoma multiforme; glioma; network; systems biology; systems genetics