Abstract 1824: The non-coding RNA landscape of lung, liver and breast cancer reveals novel tumor-associated ncRNAs, concerted regulation and unexpected tissue specificity.

Abstract

Abstract Non-coding RNA profiles in cancer are largely unknown which greatly impedes the discovery of functionally important ncRNAs in tumorigenesis as well as the generation of genome-wide libraries. Here, we define the ncRNA expression landscape of lung, breast and liver cancer as well as normal tissue from the respective organs in a large set of primary patient samples (N=150). These samples were carefully selected to have a long patient follow-up and complete clinical datasets to allow an in-depth analysis. We provide the first comprehensive map of 17000+ long ncRNAs in a broad range of human tumor and normal tissues and discovered hundreds of new ncRNAs associated with three major tumor entities. Importantly, we uncovered that ncRNA profiles are significantly more specific to the tissue of origin than patterns of protein-coding mRNAs. Also, the significant ncRNA signatures in this study demonstrate specific ncRNA patterns that are unlikely to be transcriptional background but rather the result of concerted regulation. To mimic the response to cytotoxic chemotherapy, we have also treated lung and liver cancer cells with the DNA damaging agents Cisplatin and Etoposide and found significant deregulation of long ncRNAs - reversing in part the differences seen between normal and malignant lung tissue. Importantly, one of the Cisplatin-regulated ncRNAs interacts with DNA repair factors linking it immediately to the DNA damage response. To elucidate the molecular functions of the novel ncRNAs, we used RNA affinity purification to identify the protein interaction partners. In addition, we create human knockout cells for lncRNAs using ZFN and TALEN technology to integrate RNA destabilizing elements into the human genome which yields more than 1000-fold lncRNA silencing. Our so far largest ncRNA expression map is also exploited in another way: We generate an siRNA library specifically targeting over 600 tumor-associated ncRNAs based on our profiling landscape. This comprehensive but focused library will elucidate the role of ncRNAs in tumorigenesis, viability, apoptosis and the DNA damage response. In summary, we provide the first global comprehensive map of long ncRNA expression in a broad range of human tumor and normal tissue samples and discovered many new lncRNAs associated with cancer as well as tissue-, histology- and prognosis-specific ncRNA signatures. Citation Format: Maria Polycarpou-Schwarz, Tony Gutschner, Monika Hämmerle, Anna Roth, Ashish Goyal, Stefanie Grund, Catherina Hildenbrand, Arne Warth, Thomas Longerich, Sebastian Aulmann, Joachim Rom, Michael Meister, Thomas Muley, Heike Zabeck, Sabine Schmidt, Tomi Ivacevic, Vladimir Benes, Kai Breuhahn, Philipp Schnabel, Peter Sinn, Hans Hoffmann, Peter Schirmacher, Sven Diederichs. The non-coding RNA landscape of lung, liver and breast cancer reveals novel tumor-associated ncRNAs, concerted regulation and unexpected tissue specificity. [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 1824. doi:10.1158/1538-7445.AM2013-1824