Phenotypic heterogeneity in cancer is often caused by different patterns of genetic alterations. Understanding such phenotype-genotype relationships is fundamental for the advance of personalized medicine. One of the important challenges in the area is to predict drug response on a personalized level and to understand the causes of different responses. The pathway-centric view of cancer significantly advanced the understanding of genotype-phenotype relationships. However, most network identification methods in cancer focus on identifying subnetworks that include general cancer drivers or are associated with discrete features such as cancer subtypes, hence cannot be applied directly for the analysis of continuous features like drug response. On the other hand, existing genome wide association approaches do not fully utilize the complex and heterogeneous proprieties of cancer mutational landscape. To address these challenges, we developed a computational method, named NETPHIX (NETwork-to-PHenotype assocIation with eXclusivity), which aims to identify subnetworks of genes whose genetic alterations are associated with a continuous cancer phenotype. Leveraging the properties of cancer mutations such as mutual exclusivity and the interactions among genes, we formulate the problem as an integer linear program and solve it optimally to obtain a set of associated genes. Applied to a large-scale drug screening dataset, NETPHIX uncovered gene modules significantly associated with drug responses, and many of the modules are also validated in another independent dataset. Utilizing interaction information, NETPHIX modules are functionally coherent, and can thus provide important insights into drug action.

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