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Increased entropy of signal transduction in the cancer metastasis phenotype

Teschendorff, AE; Severini, S; (2010) Increased entropy of signal transduction in the cancer metastasis phenotype. BMC Systems Biology , 4 , Article 104. 10.1186/1752-0509-4-104. Green and gold open access

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Background: The statistical study of biological networks has led to important novel biological insights, such as the presence of hubs and hierarchical modularity. There is also a growing interest in studying the statistical properties of networks in the context of cancer genomics. However, relatively little is known as to what network features differ between the cancer and normal cell physiologies, or between different cancer cell phenotypes.Results: Based on the observation that frequent genomic alterations underlie a more aggressive cancer phenotype, we asked if such an effect could be detectable as an increase in the randomness of local gene expression patterns. Using a breast cancer gene expression data set and a model network of protein interactions we derive constrained weighted networks defined by a stochastic information flux matrix reflecting expression correlations between interacting proteins. Based on this stochastic matrix we propose and compute an entropy measure that quantifies the degree of randomness in the local pattern of information flux around single genes. By comparing the local entropies in the non-metastatic versus metastatic breast cancer networks, we here show that breast cancers that metastasize are characterised by a small yet significant increase in the degree of randomness of local expression patterns. We validate this result in three additional breast cancer expression data sets and demonstrate that local entropy better characterises the metastatic phenotype than other non-entropy based measures. We show that increases in entropy can be used to identify genes and signalling pathways implicated in breast cancer metastasis and provide examples of de-novo discoveries of gene modules with known roles in apoptosis, immune-mediated tumour suppression, cell-cycle and tumour invasion. Importantly, we also identify a novel gene module within the insulin growth factor signalling pathway, alteration of which may predispose the tumour to metastasize.Conclusions: These results demonstrate that a metastatic cancer phenotype is characterised by an increase in the randomness of the local information flux patterns. Measures of local randomness in integrated protein interaction mRNA expression networks may therefore be useful for identifying genes and signalling pathways disrupted in one phenotype relative to another. Further exploration of the statistical properties of such integrated cancer expression and protein interaction networks will be a fruitful endeavour.

Title:Increased entropy of signal transduction in the cancer metastasis phenotype
Open access status:An open access publication. A version is also available from UCL Discovery.
Publisher version:http://dx.doi.org/10.1186/1752-0509-4-104
Additional information: © 2010 Teschendorff and Severini; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords:Negative breast-cancer, protein-interaction networks, systems biology, igf system, prognosis, classification, instability, modularity, database, subtype
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Wolfson Institute and Cancer Institute Administration > Cancer Institute > Research Department of Cancer Biology
UCL > School of BEAMS > Faculty of Engineering Science > Computer Science

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