A DNA methylation network interaction measure, and detection of network oncomarkers

PLoS One. 2014 Jan 6;9(1):e84573. doi: 10.1371/journal.pone.0084573. eCollection 2014.

Abstract

Epigenetic processes--including DNA methylation--are increasingly seen as having a fundamental role in chronic diseases like cancer. DNA methylation patterns offer a route to develop prognostic measures based directly on DNA measurements, rather than less-stable RNA measurements. A novel DNA methylation-based measure of the co-ordinated interactive behaviour of genes is developed, in a network context. It is shown that this measure reflects well the co-regulatory behaviour linked to gene expression (at the mRNA level) over the same network interactions. This measure, defined for pairs of genes in a single patient/sample, associates with overall survival outcome independent of known prognostic clinical features, in several independent data sets relating to different cancer types. In total, more than half a billion CpGs in over 1600 samples, taken from nine different cancer entities, are analysed. It is found that groups of gene-pair interactions which associate significantly with survival identify statistically significant subnetwork modules. Many of these subnetwork modules are shown to be biologically relevant by strong correlation with pre-defined gene sets, such as immune function, wound healing, mitochondrial function and MAP-kinase signalling. In particular, the wound healing module corresponds to an increase in co-ordinated interactive behaviour between genes for worse prognosis, and the immune module corresponds to a decrease in co-ordinated interactive behaviour between genes for worse prognosis. This measure has great potential for defining DNA-based cancer biomarkers. Such biomarkers could naturally be developed further, by drawing on the rapidly expanding knowledge base of network science.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Computational Biology / methods
  • DNA Methylation*
  • Epistasis, Genetic*
  • Gene Expression Profiling
  • Gene Regulatory Networks*
  • Humans
  • Models, Biological
  • Neoplasms / genetics
  • Neoplasms / mortality
  • Prognosis

Substances

  • Biomarkers, Tumor