Revealing the Impact of Genomic Alterations on Cancer Cell Signaling with an Interpretable Deep Learning Model.

Cancer is a disease of aberrant cellular signaling resulting from somatic genomic alterations (SGAs). Heterogeneous SGA events in tumors lead to tumor-specific signaling system aberrations. We interpret the cancer signaling system as a causal graphical model, where SGAs affect signaling proteins, propagate their effects through signal transduction, and ultimately change gene expression. To represent such a system, we developed a deep learning model called redundant-input neural network (RINN) with a transparent redundant-input architecture. Our findings demonstrate that by utilizing SGAs as inputs, the RINN can encode their impact on the signaling system and predict gene expression accurately when measured as the area under ROC curves. Moreover, the RINN can discover the shared functional impact (similar embeddings) of SGAs that perturb a common signaling pathway (e.g., PI3K, Nrf2, and TGF). Furthermore, the RINN exhibits the ability to discover known relationships in cellular signaling systems.