A network diffusion approach to inferring sample-specific function reveals functional changes associated with breast cancer

PLoS Comput Biol. 2017 Nov 30;13(11):e1005793. doi: 10.1371/journal.pcbi.1005793. eCollection 2017 Nov.

Abstract

Guilt-by-association codifies the empirical observation that a gene's function is informed by its neighborhood in a biological network. This would imply that when a gene's network context is altered, for instance in disease condition, so could be the gene's function. Although context-specific changes in biological networks have been explored, the potential changes they may induce on the functional roles of genes are yet to be characterized. Here we analyze, for the first time, the network-induced potential functional changes in breast cancer. Using transcriptomic samples for 1047 breast tumors and 110 healthy breast tissues from TCGA, we derive sample-specific protein interaction networks and assign sample-specific functions to genes via a diffusion strategy. Testing for significant changes in the inferred functions between normal and cancer samples, we find several functions to have significantly gained or lost genes in cancer, not due to differential expression of genes known to perform the function, but rather due to changes in the network topology. Our predicted functional changes are supported by mutational and copy number profiles in breast cancers. Our diffusion-based functional assignment provides a novel characterization of a tumor that is complementary to the standard approach based on functional annotation alone. Importantly, this characterization is effective in predicting patient survival, as well as in predicting several known histopathological subtypes of breast cancer.

MeSH terms

  • Algorithms
  • Breast / metabolism
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cluster Analysis
  • Computational Biology / methods*
  • Diffusion
  • Female
  • Gene Expression Profiling
  • Humans
  • Mutation
  • Protein Interaction Maps / genetics*
  • Protein Interaction Maps / physiology
  • Transcriptome / genetics*

Grants and funding

This work was partly funded by NSF DBI1564785 to SH. Part of it was done while RS was on sabbatical at UMD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.