Jan 21, 2015

Cooperation between Noncanonical Ras Network Mutations

Cell Reports
Edward C StitesKodi S Ravichandran

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.

  • References30
  • Citations8

References

Mentioned in this Paper

TP53 gene
Flow Cytometry
Biochemical Pathway
Biological Neural Networks
Tumor Suppressor Genes
NRAS gene
N-ras Genes
BRAF protein, human
Mutation, Nonsense
Genome

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