Abstract 1532: Short RNAs v2.0: isomiRs, tRFs, and rRFs represent numerous novel opportunities for developing potent, precision-medicine-aware diagnostics, prognostics, and therapeutics

Abstract

Abstract Background: It has been twenty-eight years since the first microRNA (miRNA) was reported in the worm C. elegans. Since then, researchers have discovered miRNAs in animals, plants, and viruses. They also showed that miRNAs are critical regulators of many cellular processes in homeostasis and disease. The advent of deep sequencing helped discover many novel miRNAs, pinpointed miRNAs that are dysregulated in cancers and other diseases, and established that miRNAs have isoforms (isomiRs). Deep sequencing also proved instrumental in discovering two more populous classes of short RNAs, the tRNA-derived fragments (tRFs) and the rRNA-derived fragments (rRFs). In the last decade, others and we generated strong evidence that isomiRs, tRFs, and rRFs regulate messenger RNA (mRNA) and protein abundance, directly and indirectly. Methods: IsomiRs, tRFs, and rRFs arise from precursors whose genomic distribution is non-random. Many of these precursors contain sequence segments that resemble one another's or are present in unrelated genomic sequences. These factors obfuscate the molecules’ identity and genomic origin, muddle their biogenesis details, and complicate the design of experiments. Thus, to help study isomiRs, tRFs, and rRFs we had to develop specialized tools that tackle these complications. We analyzed tens of thousands of human samples using these tools, including specimens of primary human tissues, cancer cell lines, and biofluids. Results: We were the first to show that the expression of isomiRs, tRFs, and rRFs is regimented and depends on tissue type and disease. We were also first to show that their expression additionally depends on genetic ancestry, sex, and age. Our findings highlight the involvement of isomiRs, tRFs, and rRFs in previously unsuspected regulatory interactions. These interactions are currently uncharacterized and depend on cell context and, unexpectedly, on personal attributes. These dependencies are consequential. Indeed, we showed for many cancers that specific isomiRs, tRFs, and rRFs predispose patients of a given sex or ancestry to aggressive cancer biology. Conclusions: Our pan-cancer analyses show that isomiRs, tRFs, and rRFs offer unparalleled granularity when studying normal physiology, cancer, and the molecular biology of health disparities. Improving our understanding of the molecules’ dependence on tissue, disease, and personal attributes (e.g., sex, ancestry, age) will help develop better diagnostics, prognostics, and new approaches to personalized therapies. Preliminary reports provide strong evidence in this regard. Because very little is known currently about these three classes of short RNAs, data-driven approaches will be essential to all these efforts. Citation Format: Isidore Rigoutsos. Short RNAs v2.0: isomiRs, tRFs, and rRFs represent numerous novel opportunities for developing potent, precision-medicine-aware diagnostics, prognostics, and therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1532.