Revealing global regulatory perturbations across human cancers.
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.
Goodarzi
Hani
H
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Elemento
Olivier
O
Tavazoie
Saeed
S
D002051:Burkitt Lymphoma / Q000235:genetics; D016000:Cluster Analysis; D019295:Computational Biology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics; D050436:Regulatory Elements, Transcriptional; D012984:Software; D001749:Urinary Bladder Neoplasms / Q000235:genetics*