title: Cooperation between Noncanonical Ras Network Mutations.
abstract: Cancer develops after the acquisition of a collection of mutations that together create the cancer phenotype. How collections of mutations work together within a cell and whether there is selection for certain combinations of mutations are not well understood. We investigated this problem with a mathematical model of the Ras signaling network, including a computational random mutagenesis. Modeling and subsequent experiments revealed that mutations of the tumor suppressor gene NF1 can amplify the effects of other Ras pathway mutations, including weakly activating, noncanonical Ras mutants. Furthermore, analyzing recently available, large, cancer genomic data sets uncovered increased co-occurrence of NF1 mutations with mutations in other Ras network genes. Overall, these data suggest that combinations of Ras pathway mutations could serve the role of cancer "driver." More generally, this work suggests that mutations that result in network instability may promote cancer in a manner analogous to genomic instability.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Clinical Translational Research Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA. Electronic address: estites@path.wustl.edu.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stites
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, University of Virginia, Charlottesville, VA 22908, USA; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Trampont
authors.affiliation: Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA; Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Lisa B
authors.initials: LB
authors.lastname: Haney
authors.affiliation: Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA; Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Scott F
authors.initials: SF
authors.lastname: Walk
authors.affiliation: Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA; Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran