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Nat Rev Cancer. 2017 Feb;17(2):116-130. doi: 10.1038/nrc.2016.124. Epub 2016 Dec 15.

The recurrent architecture of tumour initiation, progression and drug sensitivity.

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Department of Systems Biology, Columbia University, and the Departments of Biomedical Informatics, Biochemistry and Molecular Biophysics, JP Sulzberger Columbia Genome Center, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
DarwinHealth, Inc., 3960 Broadway, Suite 540, New York, New York 10032, USA.


Recent studies across multiple tumour types are starting to reveal a recurrent regulatory architecture in which genomic alterations cluster upstream of functional master regulator (MR) proteins, the aberrant activity of which is both necessary and sufficient to maintain tumour cell state. These proteins form small, hyperconnected and autoregulated modules (termed tumour checkpoints) that are increasingly emerging as optimal biomarkers and therapeutic targets. Crucially, as their activity is mostly dysregulated in a post-translational manner, rather than by mutations in their corresponding genes or by differential expression, the identification of MR proteins by conventional methods is challenging. In this Opinion article, we discuss novel methods for the systematic analysis of MR proteins and of the modular regulatory architecture they implement, including their use as a valuable reductionist framework to study the genetic heterogeneity of human disease and to drive key translational applications.

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