Revealing global regulatory perturbations across human cancers.
Mol Cell
; 36(5): 900-11, 2009 Dec 11.
Article
en En
| MEDLINE
| ID: mdl-20005852
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Neoplasias de la Vejiga Urinaria
/
Programas Informáticos
/
Regulación Neoplásica de la Expresión Génica
/
Elementos Reguladores de la Transcripción
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Mol Cell
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos