A Network-Based Model of Oncogenic Collaboration for Prediction of Drug Sensitivity

Frontiers in Genetics
Ted G LaderasKemal Sönmez

Abstract

Tumorigenesis is a multi-step process, involving the acquisition of multiple oncogenic mutations that transform cells, resulting in systemic dysregulation that enables proliferation, invasion, and other cancer hallmarks. The goal of precision medicine is to identify therapeutically-actionable mutations from large-scale omic datasets. However, the multiplicity of oncogenes required for transformation, known as oncogenic collaboration, makes assigning effective treatments difficult. Motivated by this observation, we propose a new type of oncogenic collaboration where mutations in genes that interact with an oncogene may contribute to the oncogene's deleterious potential, a new genomic feature that we term "surrogate oncogenes." Surrogate oncogenes are representatives of these mutated subnetworks that interact with oncogenes. By mapping mutations to a protein-protein interaction network, we determine the significance of the observed distribution using permutation-based methods. For a panel of 38 breast cancer cell lines, we identified a significant number of surrogate oncogenes in known oncogenes such as BRCA1 and ESR1, lending credence to this approach. In addition, using Random Forest Classifiers, we show that these significant ...Continue Reading

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Citations

Jun 20, 2019·Frontiers in Pharmacology·Steven R ChamberlinShannon McWeeney

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Software Mentioned

STRING
R Package
HotNets
MutSigCV
HPRD
PanGEA PanCancer portal
rpart
GISTIC
MuSiC
R

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