ORN: Inferring patient-specific dysregulation status of pathway modules in cancer with OR-gate Network

Pathway level understanding of cancer plays a key role in precision oncology. However, the current amount of high-throughput data cannot support the elucidation of full pathway topology. In this study, instead of directly learning the pathway network, we adapted the probabilistic OR gate to model the modular structure of pathways and regulon. The resulting model, OR-gate Network (ORN), can simultaneously infer pathway modules of somatic alterations, patient-specific pathway dysregulation status, and downstream regulon. In a trained ORN, the differentially expressed genes (DEGs) in each tumour can be explained by somatic mutations perturbing a pathway module. Furthermore, the ORN handles one of the most important properties of pathway perturbation in tumours, the mutual exclusivity. We have applied the ORN to lower-grade glioma (LGG) samples and liver hepatocellular carcinoma (LIHC) samples in TCGA and breast cancer samples from METABRIC. Both datasets have shown abnormal pathway activities related to immune response and cell cycles. In LGG samples, ORN identified pathway modules closely related to glioma development and revealed two pathways closely related to patient survival. We had similar results with LIHC samples. Additional results from the METABRIC datasets showed that ORN could characterize critical mechanisms of cancer and connect them to less studied somatic mutations (e.g., BAP1, MIR604, MICAL3, and telomere activities), which may generate novel hypothesis for targeted therapy. Author summary Cellular functions are carried out by a set of gene products. Mutation of a single gene is often sufficient to disrupt certain biological functions and promote tumorigenesis. Therefore, genes participating in the same function are less likely to mutate in the same sample. Such phenomenon is called "mutual exclusivity". In this study, our algorithm (ORN) has utilized this property to identify gene-level mutations that affect similar biological functions. It also considers mutations' impact on mRNA expression. Functional modules identified by ORN tends to be mutually exclusive while causing similar differential expression profiles. When we applied ORN to lower-grade glioma and liver cancer datasets, we have identified gene modules significantly related to patient survival. Furthermore, across different types of cancer, ORN has connected well-known cancer driver mutations with genes whose functions remain unclear. These connections, once validated, can generate novel hypothesis for biologist to further investigate cancer mechanism and develop targeted therapy.