West, JA; (2014) Network Physics in Cancer and Ageing. Doctoral thesis , UCL (University College London).

Abstract

An entry point for network physics into cancer genomics is via the interpretation of the cell as a dynamic molecular interaction network. Although there are limitations to our current knowledge of the protein interaction network, it remains the natural context to integrate and interpret omic data. The systems-level principles of genomic and epigenomic data with respect to the protein interaction network are explored. Firstly, by building models of signalling flows at the phenotype level, it is shown that increased network entropy is a hallmark of cancer both locally and globally. From the perspective of dynamical systems theory this result may explain the overall robustness of cancer cells. Genes implicated in cell proliferation and cell-cycle, many of which are oncogenes are found to be associated with decreases in network entropy, with possible implications for identifying drug targets. Changes in disorder are also explored at the genomic level and it is shown that copy number changes in cancer lead to increased sequential disorder along the genome associated with different cancer types, grades and distal metastasis. Following an exploration of epigenetic inter-cellular diversity at stem cell loci, we discover community structure in epigenomic changes associated with cancer and ageing. This reveals several pathways robustly identified to be implicated in ageing that would not have been found without an integrative approach. The protein interaction network topology of genes with such age-associated changes in DNA methylation is investigated and shown to be peripheral but synergistic with other classes of age and disease-related genes.

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