Abstract
Cross-talk among abnormal pathways widely occurs in human cancer and generally leads to insensitivity to cancer treatment. Moreover, alterations in the abnormal pathways are not limited to single molecular level. Therefore, we proposed a strategy that integrates a large number of biological sources at multiple levels for systematic identification of cross-talk among risk pathways in cancer by random walk on protein interaction network. We applied the method to multi-Omics breast cancer data from The Cancer Genome Atlas (TCGA), including somatic mutation, DNA copy number, DNA methylation and gene expression profiles. We identified close cross-talk among many known cancer-related pathways with complex change patterns. Furthermore, we identified key genes (linkers) bridging these cross-talks and showed that these genes carried out consistent biological functions with the linked cross-talking pathways. Through identification of leader genes in each pathway, the architecture of cross-talking pathways was built. Notably, we observed that linkers cooperated with leaders to form the fundamentation of cross-talk of pathways which play core roles in deterioration of breast cancer. As an example, we observed that KRAS showed a direct connection to numerous cancer-related pathways, such as MAPK signaling pathway, suggesting that it may be a central communication hub. In summary, we offer an effective way to characterize complex cross-talk among disease pathways, which can be applied to other diseases and provide useful information for the treatment of cancer.
Highlights
IntroductionResearchers have witnessed the complexity and redundancy of molecular mechanisms in mammalian cells [1,2]
During the last decade, researchers have witnessed the complexity and redundancy of molecular mechanisms in mammalian cells [1,2]
By application of our method to multi-omics data of breast cancer from The Cancer Genome Atlas (TCGA), we identified risk pathways by considering different combinations of molecular changes at different levels, and built the pathway cross-talk network associated with breast cancer
Summary
Researchers have witnessed the complexity and redundancy of molecular mechanisms in mammalian cells [1,2]. Such complexity and redundancy are mostly attributed to the cross-talk among various biological pathways [3]. The development of cancer is dependent on complex cross-talk among abnormal biological pathways, which extremely increase the difficulty of cancer treatment, since their complexity and redundancy. The inhibition of only one or a few target genes cannot restore the abnormal cross-talk of pathways and cannot achieve the desired treatment outcomes [4]. Recent studies have begun to reveal the cross-talk between various biological pathways; these represent only the tip of the iceberg
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
