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Cancer Res. 2019 Apr 17. pii: canres.0789.2019. doi: 10.1158/0008-5472.CAN-19-0789. [Epub ahead of print]

tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities.

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Computational Medicine Center, Thomas Jefferson University.
Computational Medicine Center, Thomas Jefferson University, Sidney Kimmel Medical College.
Computational Medicine Center, Thomas Jefferson University


tRNA-derived fragments (tRFs) are a class of potent regulatory RNAs. We mined the datasets from The Cancer Genome Atlas representing 32 cancer types with a deterministic and exhaustive pipeline for tRNA fragments. We found that mitochondrial tRNAs contribute disproportionally more tRFs than the nuclear ones. Through integrative analyses, we uncovered a multitude of statistically significant and context-dependent associations between the identified tRFs and mRNAs. In many of the 32 cancer types, these associations involve mRNAs from developmental processes, receptor tyrosine kinase signaling, the proteasome, and metabolic pathways that include glycolysis, oxidative phosphorylation, and ATP synthesis. Even though the pathways are common to multiple cancers, the association of specific mRNAs with tRFs depend on and differ from cancer to cancer. The associations between tRFs and mRNAs extend to genomic properties as well: specifically, tRFs are positively correlated with shorter genes that have a higher density in repeats, such as ALUs, MIRs, and ERVLs. Conversely, tRFs are negatively correlated with longer genes that have a lower repeat density, suggesting a possible dichotomy between cell proliferation and differentiation. Analyses of bladder, lung, and kidney cancer data indicate that the tRF-mRNA wiring can also depend on a patient's sex; sex-dependent associations involve cyclin-dependent kinases in bladder cancer, the MAPK signaling pathway in lung cancer, and purine metabolism in kidney cancer. Taken together, these findings suggest diverse and wide-ranging roles for tRFs and highlight the extensive interconnections of tRFs with key cellular processes and human genomic architecture.

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