A network-based model of oncogenic collaboration for prediction of drug sensitivity

Ted G. Laderas, Laura Heiser, Mustafa (Kemal) Sonmez

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 surrogate oncogenes predict drug sensitivity for 74 drugs in the breast cancer cell lines with a mean error rate of 30.9%. Additionally, we show that surrogate oncogenes are predictive of survival in patients. The surrogate oncogene framework incorporates unique or rare mutations from a single sample, and therefore has the potential to integrate patient-unique mutations into drug sensitivity predictions, suggesting a new direction in precision medicine and drug development. Additionally, we show the prevalence of significant surrogate oncogenes in multiple cancers from The Cancer Genome Atlas, suggesting that surrogate oncogenes may be a useful genomic feature for guiding pancancer analyses and assigning therapies across many tissue types.

Original languageEnglish (US)
Article number00341
JournalFrontiers in Genetics
Volume6
Issue numberDEC
DOIs
StatePublished - 2015

Fingerprint

Oncogenes
Pharmaceutical Preparations
Mutation
Precision Medicine
Breast Neoplasms
Protein Interaction Maps
Cell Line
Neoplasms
Atlases
Carcinogenesis
Genome

Keywords

  • Breast neoplasms
  • Drug sensitivity
  • Network
  • Oncogenic collaboration
  • Survival

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Genetics(clinical)

Cite this

A network-based model of oncogenic collaboration for prediction of drug sensitivity. / Laderas, Ted G.; Heiser, Laura; Sonmez, Mustafa (Kemal).

In: Frontiers in Genetics, Vol. 6, No. DEC, 00341, 2015.

Research output: Contribution to journalArticle

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