Loss-of-function uORF mutations in human malignancies

Schulz J., Mah N., Neuenschwander M., Kischka T., Ratei R., Schlag P., Castaños-Vélez E., Fichtner I., Tunn P., Denkert C., Klaas O., Berdel W., Von Kries J., Makalowski W., Andrade-Navarro M., Leutz A., Wethmar K.

Zusammenfassung

URFs and validated uORF-mediated translational control as a commonly used 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, multiplexed identifier-tagged 404 uORF translation initiation sites of 83 human tyrosine kinases and 49 other proto-oncogenes into 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 final revealed another 53 non-recurrent somatic mutations functionally deleting 22 uORF initiation and 31 follow-up codons, respectively. Initiation and termination codons in human cancer. The insufficient coverage of uORF regions in current whole exome sequencing datasets demands for future genome-wide analyzes to ultimately define the contribution of uORF-mediated translational deregulation in oncogenesis. Computational analysis of whole exome sequencing datasets of 464 colon adenocarcinomas final revealed another 53 non-recurrent somatic mutations functionally deleting 22 uORF initiation and 31 follow-up codons, respectively. Initiation and termination codons in human cancer. The insufficient coverage of uORF regions in current whole exome sequencing datasets demands for future genome-wide analyzes to ultimately define the contribution of uORF-mediated translational deregulation in oncogenesis. Computational analysis of whole exome sequencing datasets of 464 colon adenocarcinomas final revealed another 53 non-recurrent somatic mutations functionally deleting 22 uORF initiation and 31 follow-up codons, respectively. Initiation and termination codons in human cancer. The insufficient coverage of uORF regions in current whole exome sequencing datasets demands for future genome-wide analyzes to ultimately define the contribution of uORF-mediated translational deregulation in oncogenesis. Initiation and termination codons in human cancer. The insufficient coverage of uORF regions in current whole exome sequencing datasets demands for future genome-wide analyzes to ultimately define the contribution of uORF-mediated translational deregulation in oncogenesis. Initiation and termination codons in human cancer. The insufficient coverage of uORF regions in current whole exome sequencing datasets demands for future genome-wide analyzes to ultimately define the contribution of uORF-mediated translational deregulation in oncogenesis.