摘要：SummaryPhenotypic 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. We develop a computational method, named NETPHIX (NETwork-to-PHenotype association with eXclusivity) to identify subnetworks of genes whose genetic alterations are associated with drug response or other continuous cancer phenotypes. Leveraging interaction information among genes and properties of cancer mutations such as mutual exclusivity, we formulate the problem as an integer linear program and solve it optimally to obtain a subnetwork of associated genes. Applied to a large-scale drug screening dataset, NETPHIX uncovered gene modules significantly associated with drug responses. Utilizing interaction information, NETPHIX modules are functionally coherent and can thus provide important insights into drug action. In addition, we show that modules identified by NETPHIX together with their association patterns can be leveraged to suggest drug combinations.Graphical AbstractDisplay OmittedHighlights•NETPHIX identifies mutated subnetworks associated with a continuous phenotype•It can aid the identification of mutated modules associated with drug response•NETPHIX modules can be used to predict drug response and infer drug combinations•NETPHIX uncovers subnetworks using Integer Linear Programming optimizationBiological Sciences; Bioinformatics; Cancer Systems Biology
