Revealing global regulatory perturbations across human cancers. Academic Article uri icon

Overview

abstract

  • The discovery of pathways and regulatory networks whose perturbation contributes to neoplastic transformation remains a fundamental challenge for cancer biology. We show that such pathway perturbations, and the cis-regulatory elements through which they operate, can be efficiently extracted from global gene expression profiles. Our approach utilizes information-theoretic analysis of expression levels, pathways, and genomic sequences. Analysis across a diverse set of human cancers reveals the majority of previously known cancer pathways. Through de novo motif discovery we associate these pathways with transcription-factor binding sites and miRNA targets, including those of E2F, NF-Y, p53, and let-7. Follow-up experiments confirmed that these predictions correspond to functional in vivo regulatory interactions. Strikingly, the majority of the perturbations, associated with putative cis-regulatory elements, fall outside of known cancer pathways. Our study provides a systems-level dissection of regulatory perturbations in cancer-an essential component of a rational strategy for therapeutic intervention and drug-target discovery.

publication date

  • December 11, 2009

Research

keywords

  • Gene Expression Regulation, Neoplastic
  • Regulatory Elements, Transcriptional
  • Software
  • Urinary Bladder Neoplasms

Identity

PubMed Central ID

  • PMC2900319

Scopus Document Identifier

  • 71149084382

Digital Object Identifier (DOI)

  • 10.1093/carcin/bgn073

PubMed ID

  • 20005852

Additional Document Info

volume

  • 36

issue

  • 5