Signal-Oriented Pathway Analyses Reveal a Signaling Complex as a Synthetic Lethal Target for p53 Mutations.

摘要: Defining processes that are synthetic lethal with p53 mutations in cancer cells may reveal possible therapeutic strategies. In this study, we report the development of a signal-oriented computational framework for pathway discovery context. We applied our bipartite graph-based functional module algorithm to identify transcriptomic modules abnormally expressed multiple tumors, such genes were likely regulated by common, perturbed signal. For each module, weighted k-path merge search set somatic genome alterations (SGA) signal, is, candidate members regulate module. Computational evaluations indicated methods-identified pathways SGA. particular, analyses revealed SGA affecting TP53, PTK2, YWHAZ, and MED1 signals promote cell proliferation, anchor-free colony formation, epithelial-mesenchymal transition (EMT). These proteins formed signaling complex mediates these oncogenic coordinated fashion. Disruption knocking down or attenuated reversed phenotypes caused mutant manner. This searching targets is applicable all types, thus potentially impacting precision medicine cancer. Cancer Res; 76(23); 6785-94. ©2016 AACR.