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Loss-of-function uORF mutations in human malignancies

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Item Type:Article
Title:Loss-of-function uORF mutations in human malignancies
Creators Name:Schulz, J. and Mah, N. and Neuenschwander, M. and Kischka, T. and Ratei, R. and Schlag, P.M. and Castaños-Vélez, E. and Fichtner, I. and Tunn, P.U. and Denkert, C. and Klaas, O. and Berdel, W.E. and von Kries, J.P. and Makalowski, W. and Andrade-Navarro, M.A. and Leutz, A. and Wethmar, K.
Abstract:Ribosome profiling revealed widespread translational activity at upstream open reading frames (uORFs) and validated uORF-mediated translational control as a commonly repressive mechanism of gene expression. Translational activation of proto-oncogenes through loss-of-uORF mutations has been demonstrated, yet a systematic search for cancer-associated genetic alterations in uORFs is lacking. Here, we applied a PCR-based, multiplex identifier-tagged deep sequencing approach to screen 404 uORF translation initiation sites of 83 human tyrosine kinases and 49 other proto-oncogenes in 308 human malignancies. We identified loss-of-function uORF mutations in EPHB1 in two samples derived from breast and colon cancer, and in MAP2K6 in a sample of colon adenocarcinoma. Both mutations were associated with enhanced translation, suggesting that loss-of-uORF-mediated translational induction of the downstream main protein coding sequence may have contributed to carcinogenesis. Computational analysis of whole exome sequencing datasets of 464 colon adenocarcinomas subsequently revealed another 53 non-recurrent somatic mutations functionally deleting 22 uORF initiation and 31 uORF termination codons, respectively. These data provide evidence for somatic mutations affecting uORF initiation and termination codons in human cancer. The insufficient coverage of uORF regions in current whole exome sequencing datasets demands for future genome-wide analyses to ultimately define the contribution of uORF-mediated translational deregulation in oncogenesis.
Keywords:5' Untranslated Regions, Carcinogenesis, EphB1 Receptor, Genome-Wide Association Study, HEK293 Cells, High-Throughput Nucleotide Sequencing, Luciferases, MAP Kinase Kinase 6, Mutation, Neoplasm Proteins, Neoplasms, Open Reading Frames, Protein-Tyrosine Kinases, Proto-Oncogenes, Reporter Genes, Terminator Codon, Translational Peptide Chain Initiation, Tumor Cell Line
Source:Scientific Reports
ISSN:2045-2322
Publisher:Nature Publishing Group (U.K.)
Volume:8
Number:1
Page Range:2395
Date:5 February 2018
Official Publication:https://doi.org/10.1038/s41598-018-19201-8
PubMed:View item in PubMed

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