Identifying cellular cancer mechanisms through pathway-driven data integration

Abstract

Motivation Cancer is a genetic disease in which accumulated mutations of driver genes induce a functional reorganisation of the cell by reprogramming cellular pathways. Current approaches identify cancer pathways as those most internally perturbed by gene expression changes. However, driver genes characteristically perform hub roles between pathways. Therefore, we hypothesise that cancer pathways should be identified by changes in their pathway-pathway relationships. Results To learn an embedding space that captures the relationships between pathways in a healthy cell, we propose pathway-driven non-negative matrix tri-factorisation (PNMTF). In this space, we determine condition-specific (i.e., diseased and healthy) embeddings of pathways and genes. Based on these embeddings, we define our ‘NMTF centrality’ to measure a pathway’s or gene’s functional importance, and our ‘moving-distance’, to measure the change in its functional relationships. We combine both measures to predict 15 genes and pathways involved in four major cancers, predicting 60 gene-cancer associations in total, covering 28 unique genes. To further exploit driver genes’ tendency to perform hub roles, we model our network data using graphlet-adjacency, which considers nodes adjacent if their interaction patterns form specific shapes (e.g., paths or triangles). We find that the predicted genes rewire pathway-pathway interactions in the immune system and provide literary evidence that many are druggable (15/28) and implicated in the associated cancers (47/60). We predict six druggable cancer-specific drug targets. Availability The source code is available at: https://gitlab.bsc.es/swindels/pathway_driven_nmtf Supplementary information Supplementary data are available at Bioinformatics online.

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