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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.

MicroRNAs (miRs) have been repeatedly linked to tumorigenesis and tumor progression, suggesting their potential value as biomarkers and targets for therapeutic intervention. Recent evidence suggests that mRNAs compete for binding and regulation by a finite pool of miRs, thus regulating each other as competitive endogenous RNAs (ceRNAs). The extent of this new regulatory layer and its potential to alter the expression of cancer genes has been shown in several tumor types, but the actual impact of ceRNA interactions on disease remains unclear. In this study, using TCGA (The Cancer Genome Atlas) tumor datasets, we provide evidence that ceRNA play an important role in tumor etiology. Leveraging millions of shRNA-mediated perturbations from LINCS (Library of Integrated Network-based Cellular Signatures), we extensively validated ceRNA interactions in breast and prostate cancer. Moreover, we identified over 160,000 ceRNA interactions that are conserved across tumor types despite being implemented by miR programs with tumor type-specific expression. We present evidence that these ultraconserved interactions are mechanistically responsible for the dysregulation of the majority of oncogenes and tumor suppressors through TCGA-profiled genomic alteration of their cognate ceRNA regulators. Using targeted biochemical validation in cell lines, we verified the potential of ceRNA regulators to target ESR1, an established oncogene and drug target in breast cancer, and APC, an established tumor suppressor in colon adenocarcinoma. Our analysis suggests that ceRNA interactions are implemented through competition for multiple miRNAs, rendering them virtually independent of single miRNA kinetics and availability, and more likely to be conserved across contexts. Using TCGA samples, we demonstrated that conserved ceRNA interactions enable systematic identification of genomic alterations that contribute to aberrant expression of hundreds of cancer genes in each of eight distinct tumor contexts. We submit this network as a resource for analyzing ceRNA regulation in datasets where reverse engineering context-specific networks is infeasible due to low sample number or lack of miRNA expression profiles. Citation Format: Hua-Sheng Chiu, Xuerui Yang, María Rodríguez Martínez, Archana Iyer, Pavel Sumazin, Andrea Califano. Highly conserved ceRNA regulatory interactions cooperate with genomic variability to modulate drivers of tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5231. doi:10.1158/1538-7445.AM2013-5231

By analyzing gene expression data in gliobastoma in combination with matched microRNA profiles, we have uncovered a post-transcriptional regulation layer of surprising magnitude, comprising over 248,000 microRNA -mediated interactions. These include ∼7,000 genes whose transcripts act as microRNA ‘sponges’ and 148 genes that act through alternative, non-sponge interactions. Biochemical analyses in cell lines confirmed that this network regulates established drivers of tumor initiation and subtype, including PTEN, PDGFRA, RB1, VEGFA, STAT3, and RUNX1, suggesting that these interactions mediate crosstalk between canonical oncogenic pathways. RNA silencing of 13 microRNA-mediated PTEN regulators, whose locus deletions are predictive of PTEN expression variability, was sufficient to downregulate PTEN in a 3′ UTR-dependent manner and to increase tumor-cell growth rates. Thus, this microRNA -mediated network provides a mechanistic, experimentally validated rationale for the loss of PTEN expression in a large number of glioma samples with an intact PTEN locus. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4186. doi:1538-7445.AM2012-4186

By analyzing gene expression data in gliobastoma in combination with matched microRNA profiles, we have uncovered a post-transcriptional regulation layer of surprising magnitude, comprising hundreds of thousands of microRNA -mediated interactions. These include ~7,000 genes whose transcripts act as microRNA ‘sponges’ and 148 genes that act through alternative, non-sponge interactions. Biochemical analyses in cell lines confirmed that this network regulates established drivers of tumor initiation and subtype, including PTEN, PDGFRA, RB1, VEGFA, STAT3, and RUNX1, suggesting that these interactions mediate crosstalk between canonical oncogenic pathways. RNA silencing of 13 microRNA-mediated PTEN regulators, whose locus deletions are predictive of PTEN expression variability, was sufficient to downregulate PTEN in a 3′ UTR-dependent manner and to increase tumor-cell growth rates. Thus, this microRNA-mediated network provides a mechanistic, experimentally validated rationale for the loss of PTEN expression in a large number of glioma samples with an intact PTEN locus. Recently, we extended this work to three other tumor types, showing that microRNA-mediated interactions propagate the effects of genetic alterations to regulate distal oncogenes and tumor suppressors in multiple cancers. Our results suggest that, although implemented by context-specific factors, hundreds of thousands of these interactions are context-independent. Note: This abstract was not presented at the conference because the presenter was unable to attend. Citation Format: Pavel Sumazin, Hua-Sheng Chiu, Andrea Califano. microRNA-mediated interactions regulate established oncongenic pathways in cancer [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A14.