Abstract IA14: Genomic alterations dysregulate cancer genes by modulating microRNA activity

Abstract

Abstract microRNAs play key roles in cancer etiology, and recent evidence suggests that targets of the same microRNA programs are stoichiometrically coupled via a competitive endogenous RNA (ceRNA) mechanism. Consequently, aberrant expression of multiple targets of the same microRNA program dysregulate coupled ceRNA- oncogenes and tumor suppressors. We computationally inferred and experimentally validated that coordinated copy number and methylation alterations contribute to physiologically significant in-trans dysregulation of hundreds of coupled oncogenes and tumor suppressors in multiple tumor contexts. Both high-throughput perturbation assays and low-throughput mutational assays confirmed significant ceRNA-mediated regulation of cancer genes in eight tumor contexts, including ESR1 and APC in breast and colon cancer, respectively. Our analysis infers roles for previously uncharacterized genomic alterations and it suggests that ceRNA-mediated interactions account for a substantial fraction of cancer's missing genomic variability. Citation Format: Hua-Sheng Chiu, Xuerui Yang, Andrea Califano, Pavel Sumazin. Genomic alterations dysregulate cancer genes by modulating microRNA activity. [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 IA14.