Deregulation of cell signaling pathways plays a crucial role in the development of tumors. The identification of such pathways requires effective analysis tools that facilitate the interpretation of expression differences. Here, we present a novel and highly efficient method for identifying deregulated subnetworks in a regulatory network. Given a score for each node that measures the degree of deregulation of the corresponding gene or protein, the algorithm computes the heaviest connected subnetwork of a specified size reachable from a designated root node. This root node can be interpreted as a molecular key player responsible for the observed deregulation. To demonstrate the potential of our approach, we analyzed three gene expression datasets. In one scenario, we compared expression profiles of nonmalignant primary mammary epithelial cells derived from BRCA1 mutation carriers and of epithelial cells without BRCA1 mutation. Our results suggest that oxidative stress plays an important role in epithelial cells of BRCA1 mutation carriers and that the activation of stress proteins may result in avoidance of apoptosis leading to an increased overall survival of cells with genetic alterations. In summary, our approach opens new avenues for the elucidation of pathogenic mechanisms and for the detection of molecular key players.

An Integer Linear Programming Approach for Finding

Deregulated Subgraphs in Regulatory Networks

Christina Backes, Alexander Rurainski, Gunnar W. Klau, Oliver Müller, Daniel Stöckel, Andreas Gerasch,Jan  Küntzer, Daniela Maisel, Nicole Ludwig, Matthias Hein, Andreas Keller, Helmut Burtscher, Michael Kaufmann, Eckart Meese & Hans-Peter Lenhof