Abstract B1-20: Gene regulation by transcription factors and microRNAs in ovarian cancer

Abstract

Abstract Conventional methods to analyze genomic data do not make use of the connectivity between different data types, such as transcriptional regulation and gene expression, thereby often failing to identify the cellular processes that are unique to cancer and cancer subtypes. An example of this are the four recently characterized high-grade serous ovarian cancer transcriptomic subtypes – differentiated, immunoreactive, mesenchymal, and proliferative ovarian cancer. These subtypes have not been associated with significant differences in survival, and their discovery has not lead to the identification of subtype-specific therapies. Uncovering the regulatory mechanisms mediating differences in expression between these subtypes may identify new therapeutic interventions, and ultimately help cancer patients. We modeled regulatory networks of the four ovarian cancer subtypes using PANDA, a network inference approach that uses genomic data to search for an optimal network by modeling information flow between regulators and target genes. Because not only transcription factors, but also microRNAs play an important role in gene regulation, we modified the PANDA algorithm to account for the regulatory effects of microRNAs in addition to transcription factors (miR-PANDA, in preparation). We compared the networks defining gene regulation in each subtype using different network comparison metrics. We observed a very striking pattern in out-degree differences that suggests transcription factors and microRNAs play a major role in driving the different subtypes. Using gene set enrichment analysis on in-degree differences of target genes, we identified several cancer-related pathways that are highly targeted in specific subtypes, such as regulation of Notch signaling by microRNAs in the immunoreactive subtype, and regulation of Wnt signaling by transcription factors in the proliferative subtype. These results may point to new therapeutic interventions and advance personalized treatments for ovarian cancer patients. Citation Format: Marieke Lydia Kuijjer, Kimberly Glass, John Quackenbush. Gene regulation by transcription factors and microRNAs in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-20.