title: Signal-Oriented Pathway Analyses Reveal a Signaling Complex as a Synthetic Lethal Target for p53 Mutations.
abstract: Defining processes that are synthetic lethal with p53 mutations in cancer cells may reveal possible therapeutic strategies. In this study, we report the development of a signal-oriented computational framework for cancer pathway discovery in this context. We applied our bipartite graph-based functional module discovery algorithm to identify transcriptomic modules abnormally expressed in multiple tumors, such that the genes in a module were likely regulated by a common, perturbed signal. For each transcriptomic module, we applied our weighted k-path merge algorithm to search for a set of somatic genome alterations (SGA) that likely perturbed the signal, that is, the candidate members of the pathway that regulate the transcriptomic module. Computational evaluations indicated that our methods-identified pathways were perturbed by SGA. In particular, our analyses revealed that SGA affecting TP53, PTK2, YWHAZ, and MED1 perturbed a set of signals that promote cell proliferation, anchor-free colony formation, and epithelial-mesenchymal transition (EMT). These proteins formed a signaling complex that mediates these oncogenic processes in a coordinated fashion. Disruption of this signaling complex by knocking down PTK2, YWHAZ, or MED1 attenuated and reversed oncogenic phenotypes caused by mutant p53 in a synthetic lethal manner. This signal-oriented framework for searching pathways and therapeutic targets is applicable to all cancer types, thus potentially impacting precision medicine in cancer. Cancer Res; 76(23); 6785-94. ©2016 AACR.
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.|Center for Causal Discovery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Songjian
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.|Center for Causal Discovery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Cai
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.|Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.|Magee-Womens Research Institute, Pittsburgh, Pennsylvania.
authors.forename: Gonghong
authors.initials: G
authors.lastname: Yan
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.|Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.|Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.|Center for Causal Discovery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Vicky
authors.initials: V
authors.lastname: Chen
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.|Center for Causal Discovery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Lujia
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.|Center for Causal Discovery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Cooper
authors.affiliation: Department of Medicine, the State University of New York at Stony Brook, Stony Brook, New York.
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.affiliation: Department of Medicine, the State University of New York at Stony Brook, Stony Brook, New York.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.affiliation: Center for Causal Discovery, University of Pittsburgh, Pittsburgh, Pennsylvania. xinghua@pitt.edu leeav@upmc.edu.|University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.|Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.|Magee-Womens Research Institute, Pittsburgh, Pennsylvania.
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania. xinghua@pitt.edu leeav@upmc.edu.|Center for Causal Discovery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Lu
mesh_terms: D006801:Humans; D009154:Mutation; D015398:Signal Transduction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53