NetNorM: Capturing cancer-relevant information in somatic exome mutation data with gene networks for cancer stratification and prognosis

PLoS Comput Biol. 2017 Jun 26;13(6):e1005573. doi: 10.1371/journal.pcbi.1005573. eCollection 2017 Jun.

Abstract

Genome-wide somatic mutation profiles of tumours can now be assessed efficiently and promise to move precision medicine forward. Statistical analysis of mutation profiles is however challenging due to the low frequency of most mutations, the varying mutation rates across tumours, and the presence of a majority of passenger events that hide the contribution of driver events. Here we propose a method, NetNorM, to represent whole-exome somatic mutation data in a form that enhances cancer-relevant information using a gene network as background knowledge. We evaluate its relevance for two tasks: survival prediction and unsupervised patient stratification. Using data from 8 cancer types from The Cancer Genome Atlas (TCGA), we show that it improves over the raw binary mutation data and network diffusion for these two tasks. In doing so, we also provide a thorough assessment of somatic mutations prognostic power which has been overlooked by previous studies because of the sparse and binary nature of mutations.

MeSH terms

  • Algorithms
  • Biomarkers, Tumor / genetics*
  • Carcinogenesis / genetics
  • Chromosome Mapping / methods
  • Exome / genetics*
  • Gene Regulatory Networks / genetics*
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Predisposition to Disease / genetics
  • Genetic Testing / methods
  • Genome, Human / genetics
  • Genome-Wide Association Study / methods*
  • Humans
  • Mutation / genetics
  • Neoplasms / genetics*
  • Neoplasms / mortality*
  • Neoplasms / pathology
  • Polymorphism, Single Nucleotide / genetics*
  • Prognosis
  • Risk Assessment / methods
  • Risk Factors
  • Software
  • Survival Analysis

Substances

  • Biomarkers, Tumor
  • Genetic Markers

Grants and funding

This work was supported by the European Research Council grant ERC-SMAC-280032 (MLM, JPV), and by fellowships from the Miller Institute for Basic Research in Science and from the Fulbright Foundation (JPV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.