|Revealing global regulatory perturbations across human cancers.
|Year of Publication
|Goodarzi H, Elemento O, Tavazoie S
|2009 Dec 11
|Burkitt Lymphoma, Cluster Analysis, Computational Biology, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Lymphoma, Large B-Cell, Diffuse, Regulatory Elements, Transcriptional, Software, Urinary Bladder Neoplasms
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.
|PubMed Central ID
|DP1 OD003787-03 / OD / NIH HHS / United States
R01HG003219 / HG / NHGRI NIH HHS / United States
R01 HG003219-07 / HG / NHGRI NIH HHS / United States
1DP10D003787-01 / DP / NCCDPHP CDC HHS / United States
R01 HG003219 / HG / NHGRI NIH HHS / United States
P50 GM071508 / GM / NIGMS NIH HHS / United States
DP1 OD003787 / OD / NIH HHS / United States