Dissecting Pathway Disturbances Using Network Topology and Multi-platform Genomics Data

Complex diseases such as cancers usually result from accumulated disturbance of pathways instead of the disruptions of one or a few major genes. As opposed to single-platform analyses, it is likely that integrating diverse molecular regulatory elements and their interactions can lead to more insights on pathway-level disturbances of biological systems and their potential consequences in disease development and progression. To explore the benefit of pathway-based analysis, we focus on mutli-platform genomics, epigenomics and transcriptomics (-omics, for short) from 11 cancer types collected by the Cancer Genome Atlas (TCGA) project. Specifically, we use a well-studied oncogenetic pathway, the BRAF pathway, to investigate the relevant copy number variants, methylations and gene expressions, and quantify their effects on discovering tumor-specific aberrations across multiple tumor lineages. We also perform simulation studies to further investigate the effects of network topology and multiple omics on dissecting pathway disturbances. Our analysis shows that adding molecular regulatory elements such as copy number variants (CNVs) and/or methylations to the baseline mRNA molecules can improve our power of discovering tumorous aberrances. Also, incorporating copy number variants with the baseline mRNA molecules can be more beneficial than incorporating methylations. Moreover, employing regulatory topologies can improve the discoveries of tumorous aberrances. Finally, our analysis reveals similarities and differences among diverse cancer types based on disturbance of the BRAF pathway.