Abstract 4941: A microRNA activity map of human mesenchymal tumors: An integrative transcriptomic study
Authors: Andrew D. Kelly, Elena Fountzilas, Antonio R. Perez-Atayade, Jeffrey Goldsmith, Panagiotis A. Konstantinopoulos, Nancy Francoeur, Mick Correll, Renee Rubio, Lan Hu, Mark C. Gebhardt, John Quackenbush, Dimitrios Spentzos
Journal: Cancer Research (2012)

Abstract Background MicroRNAs (miRNAs) are nucleic acid regulators of many human mRNAs, and are associated with biological processes including cell proliferation, differentiation, and apoptosis. miRNA expression levels have been used in cancer profiling studies, but some evidence suggests that they do not fully capture miRNA regulatory activity. In this study we have integrated multiple mRNA and miRNA expression datasets to use gene expression as a surrogate for determining miRNA regulatory activity. We discovered (and validated using a paraffin-based cohort) patterns associated with cancer phenotypes and oncogenic pathways in mesenchymal tumors - a very heterogeneous class of malignancies - and we investigated possible causes for miRNA activity changes. Results Using a recently developed computational method which determines miRNA activity from changes in gene expression profiles, we identified differentially activated miRNAs between 77 normal and 135 sarcoma specimens and we validated many of these findings with microarray interrogation of an independent, paraffin-based tumor cohort of 18 samples. Among these differentially activated miRNAs are 17 with a histological subtype-specific activity pattern in comparison to normal mesenchymal tissue. We also found 81 miRNAs which exhibit a pattern common to all histological subtypes, and we identified 12 miRNAs with unique activity in osteosarcomas. In addition, we have shown that miRNA activity is imperfectly correlated with miRNA expression levels. Using next-generation miRNA sequencing we identified a specific sequence alteration which may contribute to differential activity by changing mRNA/miRNA complementarity. We then analyzed miRNA activity changes related to the RAS-pathway and found 21 miRNAs that switch from silenced to activated status in parallel with RAS activation. Importantly, nearly half of these miRNAs were predicted to regulate integral parts of the miRNA processing machinery, and our gene expression analysis revealed significant reductions of these transcripts in RAS-active tumors. This suggests an association between RAS signaling and miRNA processing in which miRNAs may attenuate their own biogenesis. Conclusions Our study represents the first gene expression-based investigation of miRNA regulatory activity in human sarcomas, and our findings indicate that miRNA activity patterns derived from integrated transcriptomic data are reproducible and biologically informative in cancer. We identified an association between RAS signaling and miRNA processing, and demonstrated a sequence alteration as a plausible cause for differential miRNA activity. Finally, our study highlights the value of systems level integrative miRNA/mRNA assessment with high-throughput genomic data, and the applicability of paraffin-tissue-derived RNA for validation of novel findings. 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 4941. doi:1538-7445.AM2012-4941